Substituted pyridotriazine compounds and uses thereof

ABSTRACT

The present disclosure relates generally to certain tricyclic compounds, pharmaceutical compositions comprising said compounds, and methods of making said compounds and pharmaceutical compositions. The compounds of the disclosure are useful in treating or preventing human immunodeficiency virus (HIV) infection.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.63/139,237, filed Jan. 19, 2021 and U.S. Provisional Application No.63/190,461, filed May 19, 2021, each of which is incorporated herein inits entirety for all purposes.

FIELD

This disclosure relates generally to certain2,3-dihydro-1H-pyrido[2,1-f][1,2,4]triazine compounds, pharmaceuticalcompositions comprising said compounds, and methods of making and usingsaid compounds and pharmaceutical compositions.

BACKGROUND

Human immunodeficiency virus infection and related diseases are a majorpublic health problem worldwide. Human immunodeficiency virus encodesthree enzymes which are required for viral replication: reversetranscriptase, protease, and integrase. Although drugs targeting reversetranscriptase and protease are in wide use and have shown effectiveness,particularly when employed in combination, toxicity and development ofresistant strains may limit their usefulness (Palella, et al. N. Engl. JMed. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001).Accordingly, there is a need for new agents that inhibit the replicationof HIV.

A goal of antiretroviral therapy is to achieve viral suppression in theHIV infected patient. Current treatment guidelines published by theUnited States Department of Health and Human Services provide thatachievement of viral suppression requires the use of combinationtherapies, i.e., several drugs from at least two or more drug classes(Panel on Antiretroviral Guidelines for Adults and Adolescents.Guidelines for the Use of Antiretroviral Agents in Adults andAdolescents Living with HIV. Department of Health and Human Services.Available athttps://files.aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.Accessed Feb. 20, 2020). In addition, decisions regarding the treatmentof HIV infected patients are complicated when the patient requirestreatment for other medical conditions. Because the standard of carerequires the use of multiple different drugs to suppress HIV, as well asto treat other conditions the patient may be experiencing, the potentialfor drug interaction is a criterion for selection of a drug regimen. Assuch, there is a need for antiretroviral therapies having a decreasedpotential for drug interactions.

In addition, the HIV virus is known to mutate in infected subjects(Tang, et al. Drugs (2012) 72 (9) e1-e25). Because of the proclivity ofthe HIV virus to mutate, there is a need for anti-HIV drugs to beeffective against a range of known HIV variants (Hurt, et al. HIV/AIDSCID (2014) 58, 423-431).

For certain patients, for example, those with difficult or limitedaccess to health care, adherence to daily oral treatment or prophylacticregimens can be challenging. Drugs that offer favorable pharmaceuticalproperties (for example, improved potency, long-acting pharmacokinetics,low solubility, low clearance, and/or other properties) are amenable toless frequent administration and provide for better patient compliance.Such improvements can, in turn, optimize drug exposure and limit theemergence of drug resistance.

SUMMARY

In some embodiments, disclosed herein are compounds of Formula I.

or a pharmaceutically acceptable salt thereof, wherein

-   -   Ar is C₆-C₁₀ aryl or six to ten membered heteroaryl containing        one, two or three heteroatoms selected from N, O, and S; wherein        the C₆-C₁₀ aryl or six to ten membered heteroaryl is optionally        substituted with 1-4 substituents independently selected from        the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl,        and C₁-C₆ alkyloxy;    -   R¹ is H, C₁-C₃ alkyl or phenyl;    -   R² is H or C₁-C₃ alkyl;    -   R³ is H or C₁-C₃ alkyl;    -   R⁴ and R⁵ are each independently H, halogen, cyano, C₁-C₆ alkyl,        C₁-C₆ alkyloxy, C₆-C₁₀ aryl, or six to ten membered heteroaryl        containing one, two or three heteroatoms selected from N, O, and        S; wherein the C₁-C₆ alkyl, C₁-C₆ alkyloxy, C₆-C₁₀ aryl, or six        to ten membered heteroaryl is optionally substituted with one        two or three groups independently selected from halogen, C₁-C₃        alkyloxy, or C₁-C₃ haloalkyloxy; or    -   R⁴ and R⁵ are joined together to form a 3-6 membered carbocyclic        ring or 4-6 membered heterocyclic ring comprising one heteroatom        selected from N, O, and S;    -   R⁶ is H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy or C₁-C₆        haloalkyl;    -   R⁷ is H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy, or C₁-C₆        haloalkyl;    -   R^(8A) and R^(8B) are independently H, C₁-C₃ alkyl or benzyl;        and    -   —X—Y— is —(CR^(13A)R^(13B))_(p)—CR⁹═CR¹⁰—, - or        —(CR^(13A)R^(13B))_(q)—CR^(11A)R^(11B)—CR^(12A)R^(12B)—; wherein        -   R⁹ is H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆            alkyloxy;        -   R¹⁰ is H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆            alkyloxy; or        -   R⁹ and R¹⁰ together with the carbons to which they are            attached form a phenyl or a 5-6 membered heteroaromatic ring            containing 1, 2, or 3 heteroatoms independently selected            from N, O, and S; wherein the phenyl or the 5-6 membered            heteroaromatic ring is optionally substituted with 1, 2, or            3 substituents independently selected from the group            consisting of halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and            C₁-C₃ alkyloxy; and        -   R^(11A), R^(11B), R^(12A), R^(12B), R^(13A), and R^(13B) are            each independently H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy;            or C₁-C₆ haloalkyl; or        -   R^(11A)R^(12A), R^(13A), and R^(13B) are each independently            H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy or C₁-C₆ haloalkyl;            and R^(11B) and R^(12B) together with the carbons to which            they are attached form a 3-6 membered carbocyclic ring;            wherein the 3-6 membered carbocyclic ring is optionally            substituted with 1, 2, or 3 substituents independently            selected from the group consisting of halogen, C₁-C₃ alkyl,            C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy;        -   p is 0 or 1;        -   q is 0 or 1;            wherein when —X—Y— is            —(CR^(13A)R^(13B))_(q)—CR^(11A)R^(11B)—CR^(12A)R^(12B)-then:    -   (i) R⁴ is halogen, cyano, C₁-C₆ alkyl, C₁-C₆ alkyloxy, C₆-C₁₀        aryl, or six to ten membered heteroaryl containing one, two or        three heteroatoms selected from N, O, and S; wherein the C₁-C₆        alkyl, C₁-C₆ alkyloxy, C₆-C₁₀ aryl, or six to ten membered        heteroaryl is optionally substituted with one two or three        groups independently selected from halogen, C₁-C₃ alkyloxy, or        C₁-C₃ haloalkyloxy; and R⁵ is H, halogen, cyano, C₁-C₆ alkyl,        C₁-C₆ alkyloxy, C₆-C₁₀ aryl, or six to ten membered heteroaryl        containing one, two or three heteroatoms selected from N, O, and        S; wherein the C₁-C₆ alkyl, C₁-C₆ alkyloxy, C₆-C₁₀ aryl, or six        to ten membered heteroaryl is optionally substituted with one        two or three groups independently selected from halogen, C₁-C₃        alkyloxy, or C₁-C₃ haloalkyloxy; or    -   (ii) R⁴ and R⁵ are joined together to form a 3-6 membered        carbocyclic ring or 4-6 membered heterocyclic ring with one        heteroatom; or    -   (iii) R^(8A) is C₁-C₃ alkyl or benzyl; or    -   (iv) R⁶ is halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy or C₁-C₆        haloalkyl.

In some embodiments, the disclosure provides pharmaceutical compositionscomprising a therapeutically effective amount of a compound of FormulaI, or pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In some embodiments, the disclosure provides a kit comprising a compoundof Formula I, or a pharmaceutically acceptable salt thereof, andinstructions for use.

In some embodiments, the disclosure provides a method of treating an HIVinfection in a human having or at risk of having the infection,comprising administering to the human a therapeutically effective amountof a compound of Formula I, a pharmaceutically acceptable salt thereof,or a pharmaceutical composition thereof.

In some embodiments, the disclosure provides a use of a compound ofFormula I, pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof, for treating an HIV infection in a human having orat risk of having the infection.

In some embodiments, the disclosure provides a compound of Formula I,pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof any, for use in a medical therapy.

In some embodiments, the disclosure provides a compound of Formula I,pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof any, for use in treating an HIV infection.

In some embodiments, the disclosure provides use of a compound ofFormula I, pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof, in the manufacture of a medicament for treating anHIV infection in a human having or at risk of having the infection.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodimentsdisclosed herein. However, one skilled in the art will understand thatthe embodiments disclosed herein may be practiced without these details.The description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the claimed subject matter, and is not intended tolimit the appended claims to the specific embodiments illustrated. Theheadings used throughout this disclosure are provided for convenienceonly and are not to be construed to limit the claims in any way.Embodiments illustrated under any heading may be combined withembodiments illustrated under any other heading.

I. Definitions

Unless the context requires otherwise, throughout the present disclosureand claims, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is as “including, but not limited to”.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment disclosed herein. Thus, the appearances of the phrases “inone embodiment” or “in an embodiment” in various places throughout thisspecification are not necessarily all referring to the same embodiment.Furthermore, the particular features, structures, or characteristics maybe combined in any suitable manner in one or more embodiments.

“Amino” refers to the —NH₂ radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Oxo” refers to the ═O substituent.

A prefix such as “C_(u-v)” or (C_(u)-C_(v)) indicates that the followinggroup has from u to v carbon atoms. For example, “C₁₋₆alkyl” or““C₁-C₆alkyl” indicates that the alkyl group has from 1 to 6 carbonatoms.

“Alkyl” refers to a straight or branched chain hydrocarbon radicalconsisting of carbon and hydrogen atoms, which is saturated, having fromone to twelve carbon atoms (C₁₋₁₂ alkyl), in certain embodiments one toeight carbon atoms (C₁₋₈alkyl) or one to six carbon atoms (C₁₋₆alkyl),or one to four carbon atoms (C₁₋₄alkyl), and which is attached to therest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl,1-methylethyl (iso-propyl), n-butyl, 1-methylpropyl (sec-butyl),2-methylpropyl (iso-butyl), 1,1-dimethylethyl (t-butyl), n-pentyl,hexyl, 3-methylhexyl, 2-methylhexyl, and the like.

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent alkane. For example, an alkylene group can have 1 to20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typicalalkylene radicals include, but are not limited to, methylene (—CH₂—),1,1 ethyl (—CH(CH₃)—), 1,2-ethyl (—CH₂CH₂—), 1,1-propyl (—CH(CH₂CH₃)—),1,2-propyl (—CH₂CH(CH₃)—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl(—CH₂CH₂CH₂CH₂—), and the like.

“Aryl” or “aromatic ring” refers to an aromatic carbocyclic group havinga single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic ortricyclic) including fused systems. As used herein, aryl has 6 to 20ring carbon atoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e.,C₆₋₁₂ aryl), or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examplesof aryl groups include, but are not limited to, phenyl, naphthyl,fluorenyl, and anthryl. Aryl, however, does not encompass or overlap inany way with heteroaryl defined below.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” or “carbocyclic ring” refers to a saturated or partiallysaturated cyclic alkyl group having a single ring or multiple ringsincluding fused, bridged, and spiro ring systems. The term “cycloalkyl”includes cycloalkenyl groups (i.e. the cyclic group having at least onedouble bond). As used herein, cycloalkyl has from 3 to 20 ring carbonatoms (i.e., C₃₋₂₀ cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂cycloalkyl), 3 to 10 ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8ring carbon atoms (i.e., C_(3-s) cycloalkyl), or 3 to 6 ring carbonatoms (i.e., C₃₋₆ cycloalkyl). Examples of cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. “Halocycloalkyl”refers to a cycloalkyl substituted with one or more halogens.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl group, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike.

“Heteroaryl” or “heteroaromatic ring” refers to an aromatic group havinga single ring, multiple rings, or multiple fused rings, with one or morering heteroatoms independently selected from nitrogen, oxygen, andsulfur. As used herein, heteroaryl includes 5 to 20 ring atoms (5 to 20membered heteroaromatic ring), 5 to 12 ring atoms (5 to 12 memberedheteroaromatic ring), 5 to 10 ring atoms (5 to 10 memberedheteroaromatic ring) or 5 to 6 ring atoms (5 to 6 memberedheteroaromatic ring); and 1 to 5 ring heteroatoms, 1 to 4 ringheteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ringheteroatom independently selected from nitrogen, oxygen, and sulfur.Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl,pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does notencompass or overlap with aryl as defined above.

“Heterocyclyl” or “heterocyclic ring” refers to a non-aromatic radicalor ring having from three to fifteen atoms wherein from one to six atomsare heteroatoms selected from the group consisting of nitrogen, oxygenand sulfur and attached to the rest of the molecule by a single bond. Incertain embodiments, “heterocyclyl” has from three to ten atoms, whereinfrom one to four atoms are heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur, or from three to seven atoms,wherein from one to two atoms are heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur. The nitrogen, carbon orsulfur atoms in the heterocyclyl may be optionally oxidized; thenitrogen atom may be optionally quaternized. As used herein,“heterocyclyl” or “heterocyclic ring” refers to rings that are saturatedunless otherwise indicated, e.g., in some embodiments “heterocyclyl” or“heterocyclic ring” refers to rings that are saturated or partiallysaturated where specified. Examples of such heterocyclyl include, butare not limited to, dioxolanyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

The embodiments disclosed herein are also meant to encompass allpharmaceutically acceptable compounds of Formula I beingisotopically-labeled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. In certainembodiments, these radiolabeled compounds are useful to help determineor measure the effectiveness of the compounds, by characterizing, forexample, the site or mode of action, or binding affinity topharmacologically important site of action. Certain isotopically-labeledcompounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa,IVb, V, Va, or Vb, for example, those incorporating a radioactiveisotope, are useful in drug and/or substrate tissue distributionstudies. The radioactive isotopes tritium, i.e., ³H, and carbon-14,i.e., ¹⁴C, are particularly useful for this purpose in view of theirease of incorporation and ready means of detection.

In certain embodiments, substitution with heavier isotopes such asdeuterium, i.e., 2H, may afford certain therapeutic advantages resultingfrom greater metabolic stability. For example, in vivo half-life mayincrease or dosage requirements may be reduced. Thus, heavier isotopesmay be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O, and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V,Va, or Vb can be prepared by techniques known to those skilled in theart or by processes analogous to those described in the Examples as setout below using an appropriate isotopically-labeled reagent in place ofthe non-labeled reagent previously employed.

The methods, compositions, kits and articles of manufacture providedherein use or include compounds (e.g., a compound of Formula I, Ia, Ib,II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb) orpharmaceutically acceptable salts thereof, in which from 1 to n hydrogenatoms attached to a carbon atom may be replaced by a deuterium atom orD, in which n is the number of hydrogen atoms in the molecule. As knownin the art, the deuterium atom is a non-radioactive isotope of thehydrogen atom. Such compounds increase resistance to metabolism, andthus are useful for increasing the half-life of compounds orpharmaceutically acceptable salts thereof, when administered to amammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of DrugMetabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Suchcompounds can be synthesized by means known in the art, for example byemploying starting materials in which one or more hydrogen atoms havebeen replaced by deuterium.

The embodiments disclosed herein are also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the embodiments disclosed hereininclude compounds produced by a process comprising administering acompound according to the embodiments disclosed herein to a mammal for aperiod of time sufficient to yield a metabolic product thereof. Suchproducts are typically identified by administering a radiolabeledcompound according to the embodiments disclosed herein in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventor circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted heterocyclyl” meansthat the heterocyclyl radical may or may not be substituted and that thedescription includes both substituted heterocyclyl radicals andheterocyclyl radicals having no substitution.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,emulsifier, or other pharmacologically inactive substance that isformulated in combination with a pharmacologically active ingredient ofa pharmaceutical composition and is compatible with the otheringredients of the formulation and suitable for use in humans ordomestic animals without undue toxicity, irritation, allergic response,and the like.

Examples of “pharmaceutically acceptable salts” of the compoundsdisclosed herein include salts derived from an appropriate base, such asan alkali metal (for example, sodium), an alkaline earth metal (forexample, magnesium), ammonium and NX₄ ⁺ (wherein X is C₁₋₄alkyl).Pharmaceutically acceptable salts of a nitrogen atom or an amino groupinclude, for example, salts of organic carboxylic acids such as acetic,trifluoroacetic, adipic, ascorbic, aspartic, butyric, camphoric,cinnamic, citric, digluconic, glutamic, glycolic, glycerophosphoric,formic, hexanoic, benzoic, lactic, fumaric, tartaric, maleic,hydroxymaleic, malonic, malic, mandelic, isethionic, lactobionic,nicotinic, oxalic, pamoic, pectinic, phenylacetic, 3-phenylpropionic,pivalic, propionic, pyruvic, salicylic, stearic, sulfanilic, tartaric,undecanoic, and succinic acids; organic sulfonic acids, such asmethanesulfonic, ethanesulfonic, camphorsulfonic, mesitylenesulfonic,benzenesulfonic, p-toluenesulfonic acids, naphthalenesulfonic, and2-naphthalenesulfonic; and inorganic acids, such as hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, and sulfamic acids.Pharmaceutically acceptable salts of a compound of a hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as Na⁺ and NX₄ ⁺ (wherein X is independently selected from H or aC₁₋₄alkyl group).

For therapeutic use, salts of active ingredients of the compoundsdisclosed herein will typically be pharmaceutically acceptable, i.e.,they will be salts derived from a physiologically acceptable acid orbase. However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a compound of Formula I or another compound of theembodiments disclosed herein. All salts, whether or not derived from aphysiologically acceptable acid or base, are within the scope of theembodiments disclosed herein.

Metal salts typically are prepared by reacting the metal hydroxide witha compound according to the embodiments disclosed herein. Examples ofmetal salts which are prepared in this way are salts containing Li⁺,Na⁺, and K⁺. A less soluble metal salt can be precipitated from thesolution of a more soluble salt by addition of the suitable metalcompound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines. Finally, it is to beunderstood that the compositions herein comprise compounds disclosedherein in their un-ionized, as well as zwitterionic form.

A “pharmaceutical composition” refers to a formulation of a compound ofthe embodiments disclosed herein and a medium generally accepted in theart for the delivery of the biologically active compound to mammals,e.g., humans. Such a medium includes all pharmaceutically acceptableexcipients.

“Effective amount” or “therapeutically effective amount” refers to anamount of a compound according to the embodiments disclosed herein,which when administered to a patient in need thereof, is sufficient toeffect treatment of disease-states, conditions, or disorders disclosedherein. Such an amount would be sufficient to elicit the biological ormedical response of a tissue system, or patient that is sought by aresearcher or clinician. The amount of a compound according to theembodiments disclosed herein which constitutes a therapeuticallyeffective amount will vary depending on such factors as the compound andits biological activity, the composition used for administration, thetime of administration, the route of administration, the rate ofexcretion of the compound, the duration of the treatment, the type ofdisease-state or disorder being treated and its severity, drugs used incombination, or coincidentally, with the compounds of the embodimentsdisclosed herein, and the age, body weight, general health, sex and dietof the patient. Such a therapeutically effective amount can bedetermined by one of ordinary skill in the art having regard to theirown knowledge, the state of the art, and this disclosure.

The terms “treating” and “treatment” as used herein are intended to meanthe administration of a compound or composition according to the presentembodiments disclosed herein to alleviate or eliminate one or moresymptoms of HIV infection and/or to reduce viral load in a patient. Incertain embodiments, the terms “treating” and “treatment” also encompassthe administration of a compound or composition according to the presentembodiments disclosed herein post-exposure of the individual to thevirus but before the appearance of symptoms of the disease, and/or priorto the detection of the virus in the blood, to prevent the appearance ofsymptoms of the disease and/or to prevent the virus from reachingdetectable levels in the blood, and the administration of a compound orcomposition according to the present embodiments disclosed herein toprevent perinatal transmission of HIV from mother to baby, byadministration to the mother before giving birth and to the child withinthe first days of life. The terms “treating” and “treatment” alsoencompass the administration of a compound or composition according tothe present embodiments disclosed herein before the exposure of theindividual to the virus (also called pre-exposure prophylaxis or PrEP),to prevent HIV infection from taking hold if the individual is exposedto the virus and/or to keep the virus from establishing a permanentinfection and/or to prevent the appearance of symptoms of the diseaseand/or to prevent the virus from reaching detectable levels in theblood. The terms “treating” and “treatment” also encompass theadministration of a compound or composition according to the presentembodiments disclosed herein both before and after the exposure of theindividual to the virus.

As used herein, the terms “preventing” and “prevention” refer to theadministration of a compound, composition, or pharmaceutically saltaccording to the present disclosure pre- or post-exposure of the humanto the virus but before the appearance of symptoms of the disease,and/or prior to the detection of the virus in the blood. The terms alsorefer to prevention of the appearance of symptoms of the disease and/orto prevent the virus from reaching detectible levels in the blood. Theterms include both pre-exposure prophylaxis (PrEP), as well aspost-exposure prophylaxis (PEP) and event driven or “on demand”prophylaxis. The terms also refer to prevention of perinataltransmission of HIV from mother to baby, by administration to the motherbefore giving birth and to the child within the first days of life. Theterms also refer to prevention of transmission of HIV through bloodtransfusion.

The term “antiviral agent” as used herein is intended to mean an agent(compound or biological) that is effective to inhibit the formationand/or replication of a virus in a human being, including but notlimited to agents that interfere with either host or viral mechanismsnecessary for the formation and/or replication of a virus in a humanbeing.

The term “inhibitor of HIV replication” as used herein is intended tomean an agent capable of reducing or eliminating the ability of HIV toreplicate in a host cell, whether in vitro, ex vivo or in vivo.

The compounds of the embodiments disclosed herein, or theirpharmaceutically acceptable salts may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)-for amino acids. Thepresent disclosure is meant to include all such possible isomers, aswell as their racemic, scalemic, and optically pure forms. Opticallyactive (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingmethods such as chromatography and fractional crystallization.Techniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are non-superimposablemirror images of one another. In any of the embodiments disclosedherein, compounds disclosed herein may be in the form of a stereoisomerthereof.

“Partially unsaturated” refers to a cyclic group which contains at leastone double bond but is not aromatic.

Substituents and multivalent groups can be attached to the remainder ofthe molecule at any position and in any orientation to produce a stablecompound. For example, the compound of Formula I.

wherein —X—Y— is defined as —CR^(13A)R^(13B)—CR⁹═CR¹⁰— include compoundsof Formula

as well as compounds of Formula

Similarly, compounds of Formula I, where —X—Y— is—CR^(11A)R^(11B)—CR^(12A)R^(12B)—, include compounds of Formula

as well as compounds of Formula

II. Compounds

Disclosed herein are compounds of Formula I.

or a pharmaceutically acceptable salt thereof, wherein

Ar is C₆-C₁₀ aryl or six to ten membered heteroaryl containing one, twoor three heteroatoms selected from N, O, and S; wherein the C₆-C₁₀ arylor six to ten membered heteroaryl is optionally substituted with 1-4substituents independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkyloxy;

R¹ is H, C₁-C₃ alkyl or phenyl;

R² is H or C₁-C₃ alkyl;

R³ is H or C₁-C₃ alkyl;

R⁴ and R⁵ are each independently H, halogen, cyano, C₁-C₆ alkyl, C₁-C₆alkyloxy, C₆-C₁₀ aryl, or six to ten membered heteroaryl containing one,two or three heteroatoms selected from N, O, and S; wherein the C₁-C₆alkyl, C₁-C₆ alkyloxy, C₆-C₁₀ aryl, or six to ten membered heteroaryl isoptionally substituted with one two or three groups independentlyselected from halogen, C₁-C₃ alkyloxy, or C₁-C₃ haloalkyloxy; or

R⁴ and R⁵ are joined together to form a 3-6 membered carbocyclic ring or4-6 membered heterocyclic ring comprising one heteroatom selected fromN, O, and S;

R⁶ is H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy or C₁-C₆ haloalkyl;

R⁷ is H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy, or C₁-C₆ haloalkyl;

R^(8A) and R^(8B) are each independently H, C₁-C₃ alkyl or benzyl; and—X—Y— is —(CR^(13A)R^(13B))_(p)—CR⁹═CR¹⁰— or—(CR^(13A)R^(13B))_(q)—CR^(11A)R^(11B)—CR^(12A)R^(12B)—; wherein

-   -   R⁹ is H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆        alkyloxy;    -   R¹⁰ is H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆        alkyloxy; or    -   R⁹ and R¹⁰ together with the carbons to which they are attached        form a phenyl or a 5-6 membered heteroaromatic ring containing        1, 2, or 3 heteroatoms independently selected from N, O, and S;        wherein the phenyl or the 5-6 membered heteroaromatic ring is        optionally substituted with 1, 2, or 3 substituents        independently selected from the group consisting of halogen,        C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy; and    -   R^(11A), R^(11B), R^(12A), R^(12B), R^(13A), and R^(13B) are        each independently H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy; or        C₁-C₆ haloalkyl; or    -   R^(11A), R^(12A), R^(13A), and R^(13B) are each independently H,        halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy; or C₁-C₆ haloalkyl; and        R^(11B) and R^(12B) together with the carbons to which they are        attached form a 3-6 membered carbocyclic ring; wherein the 3-6        membered carbocyclic ring is optionally substituted with 1, 2,        or 3 substituents independently selected from the group        consisting of halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃        alkyloxy;    -   p is 0 or 1; and    -   q is 0 or 1;

wherein when —X—Y is—(CR^(13A)R^(13B))_(q)—CR^(11A)R^(11B)—CR^(12A)R^(12B)— then

-   -   (i) R⁴ is halogen, cyano, C₁-C₆ alkyl, C₁-C₆ alkyloxy, C₆-C₁₀        aryl, or six to ten membered heteroaryl containing one, two or        three heteroatoms selected from N, O, and S; wherein the C₁-C₆        alkyl, C₁-C₆ alkyloxy, C₆-C₁₀ aryl, or six to ten membered        heteroaryl is optionally substituted with one two or three        groups independently selected from halogen, C₁-C₃ alkyloxy, or        C₁-C₃ haloalkyloxy; and R⁵ is H, halogen, cyano, C₁-C₆ alkyl,        C₁-C₆ alkyloxy, C₆-C₁₀ aryl, or six to ten membered heteroaryl        containing one, two or three heteroatoms selected from N, O, and        S, wherein the C₁-C₆ alkyl, C₁-C₆ alkyloxy, C₆-C₁₀ aryl, or six        to ten membered heteroaryl is optionally substituted with one        two or three groups independently selected from halogen, C₁-C₃        alkyloxy, or C₁-C₃ haloalkyloxy; or    -   (ii) R⁴ and R⁵ are joined together to form a 3-6 membered        carbocyclic ring or 4-6 membered heterocyclic ring with one        heteroatom; or    -   (iii) R^(8A) is C₁-C₃ alkyl or benzyl; or    -   (iv) R⁶ is halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy or C₁-C₆        haloalkyl.

In some embodiments, the compounds of Formula I provided herein have aFormula Ia:

In some embodiments, the compounds of Formula I provided herein have aFormula Ib:

In some embodiments of the compound of Formula I, Formula Ia, andFormula Ib, Ar is C₆-C₁₀ aryl or six to ten membered heteroarylcontaining one, two or three heteroatoms selected from N, O, and S;wherein the C₆-C₁₀ aryl or six to ten membered heteroaryl is optionallysubstituted with 1-4 halogens. In some embodiments, Ar is C₆-C₁₀ aryl orsix to ten membered heteroaryl containing one, two or three heteroatomsselected from N, O, and S; wherein the C₆-C₁₀ aryl or six to tenmembered heteroaryl is optionally substituted with 1-3 substituentsindependently selected from Cl and F.

In some embodiments of the compound of Formula I, Formula Ia, andFormula Ib, Ar is C₆-C₁₀ aryl or six to ten membered heteroarylcontaining one heteroatom selected from N, O, and S; wherein the C₆-C₁₀aryl or six to ten membered heteroaryl is optionally substituted with1-4 substituents independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkyloxy. In someembodiments, Ar is C₆-C₁₀ aryl or six to ten membered heteroarylcontaining one heteroatom selected from N, O, and S; wherein the C₆-C₁₀aryl or six to ten membered heteroaryl is optionally substituted with1-4 substituents independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, and C₁-C₆ alkyloxy. In some embodiments, Ar isC₆-C₁₀ aryl or six to ten membered heteroaryl containing one heteroatomselected from N, O, and S; wherein the C₆-C₁₀ aryl or six to tenmembered heteroaryl is optionally substituted with 1-4 halogens. In someembodiments, Ar is C₆-C₁₀ aryl or six to ten membered heteroarylcontaining one heteroatom selected from N, O, and S; wherein the C₆-C₁₀aryl or six to ten membered heteroaryl is optionally substituted with1-3 substituents independently selected from Cl and F.

In some embodiments of the compound of Formula I, Formula Ia, andFormula Ib, Ar is phenyl optionally substituted with 1-4 substituentsindependently selected from the group consisting of halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkyloxy. In some embodiments, Ar isphenyl optionally substituted with 1-4 substituents independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, and C₁-C₆alkyloxy. In some embodiments, Ar is phenyl optionally substituted with1-4 halogens. In some embodiments, Ar is phenyl optionally substitutedwith 1-3 substituents independently selected from Cl and F.

In some embodiments of the compound of Formula I, Formula Ia, andFormula Ib, Ar is phenyl, optionally substituted with one, two, three,or four substituents independently selected from halogen and C₁-C₆alkyloxy. In some embodiment, Ar is phenyl substituted with one, two,three, or four substituents independently selected from halo and C₁-C₄alkyloxy. In some embodiment, Ar is phenyl substituted with one, two,three, or four substituents independently selected from Cl and F.

In some embodiments of the compound of Formula I, Formula Ia, andFormula Ib, Ar is:

wherein Z is N or CR^(A);

n is 0, 1, 2, 3, or 4; and

each R^(A) is independently halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, andC₁-C₆ alkyloxy.

In some embodiments of the compound of Formula I, Formula Ia, andFormula Ib, Z is CH or N. In some embodiments, Z is CH. In someembodiments, Z is N.

In some embodiments of the compound of Formula I, Formula Ia, andFormula Ib, Ar is

n is 1, 2, 3, or 4; and each R^(A) is independently halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl and C₁-C₆ alkyloxy. In some embodiments of thecompound of Formula I, Formula Ia, and Formula Ib, Ar is

n is 1, 2, 3, or 4; and each R^(A) is independently halogen, C₁-C₆ alkyland C₁-C₆ alkyloxy. In some embodiments of the compound of Formula I,Formula Ia, and Formula Ib, Ar is

n is 1, 2, 3, or 4; and each R^(A) is independently halogen and C₁-C₆alkyloxy. In some embodiments, Ar is

n is 1, 2, 3, or 4; and each R^(A) is independently halogen and C₁-C₄alkyloxy. In some embodiments, Ar is

n is 1, 2, or 3; and each R^(A) is independently fluoro or chloro.

In some embodiments of the compound of Formula I, Formula Ia, andFormula Ib, Ar is

n is 1, 2, 3, or 4; and each R^(A) is independently halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl and C₁-C₆ alkyloxy. In some embodiments of thecompound of Formula I, Formula Ia, and Formula Ib, Ar is

n is 1, 2, 3, or 4; and each R^(A) is independently halogen, C₁-C₆ alkyland C₁-C₆ alkyloxy. In some embodiments of the compound of Formula I,Formula Ia, and Formula Ib, Ar is

n is 1, 2, 3, or 4; and each R^(A) is independently halogen and C₁-C₆alkyloxy. In some embodiments, Ar is

n is 1, 2, 3, or 4; and each R^(A) is independently halogen and C₁-C₄alkyloxy. In some embodiments, Ar is

n is 1, 2, or 3; and each R^(A) is independently fluoro or chloro.

In some embodiments of the compounds of Formula I, Formula Ia, andFormula Ib, Ar is

In some embodiments, the compounds of Formula I, Formula Ia, and FormulaIb disclosed herein, have a Formula II:

wherein n is 0, 1, 2, 3, or 4; and each R^(A) is independently halogen,C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkyloxy.

In some embodiments, the compounds of Formula I, Formula Ia, Formula Ib,and Formula II disclosed herein, have a Formula IIa:

wherein n is 0, 1, 2, 3, or 4; and each R^(A) is independently halogen,C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkyloxy.

In some embodiments, the compound of Formula I, Formula Ib, and FormulaII disclosed herein, have a Formula IIb:

wherein n is 0, 1, 2, 3, or 4; and each R^(A) is independently halogen,C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkyloxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CR^(13A)CR^(13B)—CR⁹═CR¹⁰—, wherein each R⁹, R¹⁰, R^(13A)and R^(13B) are each independently H, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl or C₁-C₆ alkyloxy; or R^(13A) and R^(13B) are eachindependently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆alkyloxy; and R⁹ and R¹⁰ together with the carbons to which they areattached form a phenyl or a 5-6 membered heteroaromatic ring containing1, 2, or 3 heteroatoms independently selected from N, O, and S; whereinthe phenyl or the 5-6 membered heteroaromatic ring is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃alkyloxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CR⁹═CR¹⁰—, wherein each R⁹ and R¹⁰ is independently H,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkyloxy; or R⁹ and R¹⁰together with the carbons to which they are attached form a phenyl or a5-6 membered heteroaromatic ring containing 1, 2, or 3 heteroatomsindependently selected from N, O, and S; wherein the phenyl or the 5-6membered heteroaromatic ring is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CH₂—CR⁹═CR¹⁰—, wherein R⁹ and R¹⁰ together with thecarbons to which they are attached form a phenyl or a 5-6 memberedheteroaromatic ring containing 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; wherein the phenyl or the 5-6 memberedheteroaromatic ring is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy. In someembodiments, —X—Y— is —CH₂—CR⁹═CR¹⁰—, wherein R⁹ and R¹⁰ together withthe carbons to which they are attached form a 5-6 memberedheteroaromatic ring containing 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; wherein the 5-6 membered heteroaromatic ringis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, and C₁-C₃ alkyloxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CR⁹═CR¹⁰—, wherein R⁹ and R¹⁰ together with the carbonsto which they are attached form a phenyl or a 5-6 memberedheteroaromatic ring containing 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; wherein the phenyl or the 5-6 memberedheteroaromatic ring is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy. In someembodiments, —X—Y— is —CR⁹═CR¹⁰—, wherein R⁹ and R¹⁰ together with thecarbons to which they are attached form a 5-6 membered heteroaromaticring containing 1, 2, or 3 heteroatoms independently selected from N, O,and S; wherein the 5-6 membered heteroaromatic ring is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃alkyloxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CH₂—CR⁹═CR¹⁰—, wherein R⁹ and R¹⁰ together with thecarbons to which they are attached form a 5-6 membered heteroaromaticring containing 1, 2, or 3 heteroatoms independently selected from N, O,and S; wherein the 5-6 membered heteroaromatic ring is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃alkyloxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CR⁹═CR¹⁰—, wherein R⁹ and R¹⁰ together with the carbonsto which they are attached form a 5-6 membered heteroaromatic ringcontaining 1, 2, or 3 heteroatoms independently selected from N, O, andS; wherein the 5-6 membered heteroaromatic ring is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃alkyloxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CH₂—CR⁹═CR¹⁰—, R⁹ and R¹⁰ together with the carbons towhich they are attached form a 5-6 membered heteroaromatic ringcontaining 1, 2, or 3 heteroatoms independently selected from N, and 0;wherein the 5-6 membered heteroaromatic ring is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CR⁹═CR¹⁰—, R⁹ and R¹⁰ together with the carbons to whichthey are attached form a 5-6 membered heteroaromatic ring containing 1,2, or 3 heteroatoms independently selected from N, and 0; wherein the5-6 membered heteroaromatic ring is optionally substituted with 1, 2, or3 substituents independently selected from the group consisting ofhalogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, R^(11A)R^(11B), R^(12A), R^(12B), R^(13A), and R^(13B) are eachindependently H, halogen, C₁-C₆ alkyl, or C₁-C₆ alkyloxy. In someembodiments, R^(11A), R^(11B), R^(12A), R^(12B), R^(13A), and R^(13B)are each independently H, halogen, or C₁-C₆ alkyloxy. In someembodiments, R^(11A), R^(11B), R^(12A), R^(12B), R^(13A), and R^(13B)are each independently H, halogen, or methoxy. In some embodiments,R^(11A), R^(11B), R^(12A), R^(12B), R^(13A) and R^(13B) are eachindependently H, fluoro, or methoxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, have a Formula III:

wherein

m is 0, 1, 2, or 3; and

each R^(B) is independently halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orC₁-C₃ alkyloxy.

In some embodiments of the compounds of Formula I, Ia, II, IIa, and III,have a Formula IIIa:

whereinm is 0, 1, 2, or 3; andeach R^(B) is independently halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orC₁-C₃ alkyloxy.

In some embodiments of the compounds of Formula I, Ib, II, IIb, and III,have a Formula IIIb:

whereinm is 0, 1, 2, or 3; andeach R^(B) is independently halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orC₁-C₃ alkyloxy.

In some embodiments of the compounds of Formula III, IIIa, and IIIb, mis 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, mis 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. Insome embodiments, m is 2. In some embodiments, m is 3.

In some embodiments of the compounds of Formula III, IIIa, and IIIb,each R^(B) is independently halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, andC₁-C₃ alkyloxy. In some embodiments, each R^(B) is independentlyhalogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl. In some embodiments, each R^(B)is independently halogen or C₁-C₃ alkyl. In some embodiments, each R^(B)is independently halogen.

In some embodiments of the compounds of Formula III, IIIa, and IIIb, mis 0, 1, or 2, and each R^(B) is independently halogen, C₁-C₃ alkyl,C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy. In some embodiments, m is 0, 1, or2, and each R^(B) is independently halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl. In some embodiments, m is 0, 1, or 2, and each R^(B) isindependently halogen or C₁-C₃ alkyl. In some embodiments, m is 0, 1, or2, and each R^(B) is independently halogen.

In some embodiments of the compounds of Formula III, IIIa, and IIIb, mis 0 or 1, and each R^(B) is independently halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, and C₁-C₃ alkyloxy. In some embodiments, m is 0 or 1, andeach R^(B) is independently halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl. Insome embodiments, m is 0 or 1, and each R^(B) is independently halogenor C₁-C₃ alkyl. In some embodiments, m is 0 or 1, and each R^(B) isindependently halogen.

In some embodiments of the compounds of Formula III, IIIa, and IIIb, mis 1 or 2, and each R^(B) is independently halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, and C₁-C₃ alkyloxy. In some embodiments, m is 1 or 2, andeach R^(B) is independently halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl. Insome embodiments, m is 1 or 2, and each R^(B) is independently halogenor C₁-C₃ alkyl. In some embodiments, m is 1 or 2, and each R^(B) isindependently halogen.

In some embodiments of the compounds of Formula III, IIIa, and IIIb, mis 1, and R^(B) is halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃alkyloxy. In some embodiments, m is, and R^(B) is halogen, C₁-C₃ alkylor C₁-C₃ haloalkyl. In some embodiments, m is 1, and R^(B) is halogen orC₁-C₃ alkyl. In some embodiments, m is 1, and R^(B) is halogen.

In some embodiments of the compounds of Formula III, IIIa, and IIIb, mis 2, and each R^(B) is independently halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, and C₁-C₃ alkyloxy. In some embodiments, m is 2, and eachR^(B) is independently halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl. In someembodiments, m is 2, and each R^(B) is independently halogen or C₁-C₃alkyl. In some embodiments, m is 2, and each R^(B) is independentlyhalogen.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, have a Formula IV:

wherein z is 0 or 1.

In some embodiments of the compounds of Formula I, Ia, II, IIa, and IV,have a Formula IVa:

wherein z is 0 or 1.

In some embodiments of the compounds of Formula I, Ib, II, IIb, and IV,have a Formula IVb:

wherein z is 0 or 1.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CR⁹═CR¹⁰—, wherein each R⁹ and R¹⁰ is independently H,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkyloxy. In someembodiments, —X—Y— is —CR⁹═CR¹⁰—, wherein each R⁹ and R¹⁰ isindependently H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In someembodiments, —X—Y— is —CR⁹═CR¹⁰—, wherein each R⁹ and R¹⁰ isindependently H, halogen, or C₁-C₆ alkyl. In some embodiments, —X—Y— is—CR⁹═CR¹⁰—, wherein each R⁹ and R¹⁰ is independently H or halogen. Insome embodiments, —X—Y— is —CR⁹═CR¹⁰—, wherein each R⁹ and R¹⁰ isindependently H or F.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CR^(11A)R^(11B)—CR^(12A)R^(12B)—, wherein each R^(11A),R^(11B), R^(12A), and R^(12B) is independently H, halogen, C₁-C₆ alkyl,C₁-C₆ alkyloxy or C₁-C₆ haloalkyl; or each R^(11A) and R^(12A) isindependently H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy, or C₁-C₆haloalkyl; and R^(11B) and R^(12B) together with the carbons to whichthey are attached form a 3-6 membered carbocyclic ring; wherein the 3-6membered carbocyclic ring is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CR^(11A)R^(11B)—CR^(12A)R^(12B)—, wherein each R^(11A),R^(11B), R^(12A), and R^(12B) is independently H, halogen, C₁-C₆ alkyl,C₁-C₆ alkyloxy or C₁-C₆ haloalkyl. In some embodiments, —X—Y— is—CR^(11A)R^(11B)—CR^(12A)R^(12B)—, wherein each R^(11A), R^(11B),R^(12A), and R^(12B) is independently H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In some embodiments, —X—Y— is—CR^(11A)R^(11B)—CR^(12A)R^(12B)—, wherein each R^(11A)R^(11B), R^(12A),and R^(12B) is independently H, halogen or C₁-C₆ alkyl. In someembodiments, —X—Y— is —CR^(11A)R^(11B)—CR^(12A)R^(12B)—, wherein eachR^(11A), R^(1B), R^(12A), and R^(12B) is independently H or halogen. Insome embodiments, —X—Y— is —CR^(11A)R^(11B)—CR^(12A)R^(12B)—, whereineach R^(11A), R^(1B), R^(12A), and R^(12B) is independently H or F. Insome embodiments, —X—Y— is —CR^(11A)R^(11B)—CR^(12A)R^(12B)—, whereineach R^(11A), R^(11B), R^(12A), and R^(12B) is H.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, —X—Y— is —CR^(11A)R^(11B)—CR^(12A)R^(12B)—, wherein each R^(11A)and R^(12A) is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy, orC₁-C₆ haloalkyl; and R^(11B) and R^(12B) together with the carbons towhich they are attached form a 3-6 membered carbocyclic ring; whereinthe 3-6 membered carbocyclic ring is optionally substituted with 1, 2,or 3 substituents independently selected from the group consisting ofhalogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, andIIb, have a Formula V:

wherein z′ is 1 or 2.

In some embodiments of the compounds of Formula I, Ia, II, IIa, and V,have a Formula Va:

wherein z′ is 1 or 2.

In some embodiments of the compounds of Formula I, Ib, II, IIb, and V,have a Formula Vb:

wherein z′ is 1 or 2.

In some embodiments of the compound of Formula V, Va, and Vb describedherein, z′ is 1. In some embodiments z′ is 2.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R^(8A) isH and R^(8B) is H, C₁-C₃ alkyl or benzyl. In some embodiments, R^(8A) isH and R^(8B) is H or C₁-C₃ alkyl. In some embodiments, R^(8A) is H andR^(8B) is H or benzyl. In some embodiments, R^(8A) is H and R^(8B) isC₁-C₃ alkyl or benzyl. In some embodiments, R^(8A) is H and R^(8B) isC₁-C₃ alkyl. In some embodiments, R^(8A) is H and R^(8B) is benzyl. Insome embodiments, both R^(8A) and R^(8B) are H.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R^(8A) isC₁-C₃ alkyl and R^(8B) is H, C₁-C₃ alkyl or benzyl. In some embodiments,R^(8A) is C₁-C₃ alkyl and R^(8B) is H or C₁-C₃ alkyl. In someembodiments, R^(8A) is C₁-C₃ alkyl and R^(8B) is H or benzyl. In someembodiments, R^(8A) is C₁-C₃ alkyl and R^(8B) is C₁-C₃ alkyl or benzyl.In some embodiments, R^(8A) is C₁-C₃ alkyl and R^(8B) is H. In someembodiments, R^(8A) is C₁-C₃ alkyl and R^(8B) is benzyl. In someembodiments, both R^(8A) and R^(8B) are independently C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R^(8A) isbenzyl and R^(8B) is H, C₁-C₃ alkyl or benzyl. In some embodiments,R^(8A) is benzyl and R^(8B) is H or C₁-C₃ alkyl. In some embodiments,R^(8A) is benzyl and R^(8B) is H or benzyl. In some embodiments, R^(8A)is benzyl and R^(8B) is C₁-C₃ alkyl or benzyl. In some embodiments,R^(8A) is benzyl and R^(8B) is C₁-C₃ alkyl. In some embodiments, R^(8A)is benzyl and R^(8B) is H. In some embodiments, both R^(8A) and R^(8B)are benzyl.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R¹ is H,C₁-C₃ alkyl or phenyl and R² is H. In some embodiments, R¹ is H orphenyl and R² is H. In some embodiments, R¹ is H or C₁-C₃ alkyl and R²is H. In some embodiments, R¹ is C₁-C₃ alkyl or phenyl and R² is H. Insome embodiments, both R¹ and R² are H. In some embodiments, R¹ is C₁-C₃alkyl and R² is H. In some embodiments, R¹ is phenyl and R² is H.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R¹ is H,C₁-C₃ alkyl or phenyl and R² is C₁-C₃ alkyl. In some embodiments, R¹ isH or phenyl and R² is C₁-C₃ alkyl. In some embodiments, R¹ is H or C₁-C₃alkyl and R² is C₁-C₃ alkyl. In some embodiments, R¹ is C₁-C₃ alkyl orphenyl and R² is C₁-C₃ alkyl. In some embodiments, R¹ is H and R² isC₁-C₃ alkyl. In some embodiments, each R¹ and R² is independently C₁-C₃alkyl. In some embodiments, R¹ is phenyl and R² is C₁-C₃ alkyl. In someembodiments, each R¹ and R² is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, described herein, each R⁴ and R⁵ isindependently H, or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionallysubstituted with one two or three groups independently selected fromhalogen, C₁-C₃ alkyloxy, or C₁-C₃ haloalkyloxy. In some embodiments, R⁴is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substitutedwith one two or three groups independently selected from halogen, C₁-C₃alkyloxy, or C₁-C₃ haloalkyloxy; and R⁵ is H or C₁-C₆ alkyl. In someembodiments, R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl isoptionally substituted with one two or three groups independentlyselected from halogen, C₁-C₃ alkyloxy, or C₁-C₃ haloalkyloxy; and R⁵ isH.

In some embodiments of the compounds of Formula IV, IVa, and IVb,described herein, R⁴ is halogen or C₁-C₆ alkyl wherein the C₁-C₆ alkylis optionally substituted with one two or three groups independentlyselected from halogen, C₁-C₃ alkyloxy, or C₁-C₃ haloalkyloxy; and R⁵ isH, halogen, or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionallysubstituted with one two or three groups independently selected fromhalogen, C₁-C₃ alkyloxy, or C₁-C₃ haloalkyloxy. In some embodiments, R⁴is halogen or C₁-C₆ alkyl wherein the C₁-C₆ alkyl is optionallysubstituted with one two or three groups independently selected fromhalogen, C₁-C₃ alkyloxy, or C₁-C₃ haloalkyloxy; and R⁵ is H, halogen, orC₁-C₆ alkyl. In some embodiments, R⁴ is halogen or C₁-C₆ alkyl whereinthe C₁-C₆ alkyl is optionally substituted with one two or three groupsindependently selected from halogen, C₁-C₃ alkyloxy, or C₁-C₃haloalkyloxy; and R⁵ is H.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, described herein, each R⁴ and R⁵ isindependently H, Me, OMe, or CH₂F. In some embodiments, R⁴ is H, Me,OMe, or CH₂F and R⁵ is H.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R⁴ and R⁵are joined together to form a 4-6 membered heterocyclic ring comprisingone heteroatom selected from N, O, and S.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R⁴ and R⁵are joined together to form a 3-6 membered carbocyclic ring.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R⁶ is H,halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments, R⁶ is H,halogen or C₁-C₆ alkyl. In some embodiments, R⁶ is halogen or C₁-C₆alkyl. In some embodiments, R⁶ is C₁-C₆ alkyl. In some embodiments, R⁶is H.

In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, and IVb, described herein, R⁷ is H, halogen,C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some embodiments, R⁷ is H, halogen,or C₁-C₆ alkyl. In some embodiments, R⁷ is halogen or C₁-C₆ alkyl. Insome embodiments, R⁷ is C₁-C₆ alkyl. In some embodiments, R⁷ is H.

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is selected from the groupconsisting of:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is selected from the groupconsisting of:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is selected from the groupconsisting of:

In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is selected from the groupconsisting of:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is selected from the groupconsisting of:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is selected from the groupconsisting of:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is selected from the groupconsisting of:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is selected from the groupconsisting of:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is selected from the groupconsisting of:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is selected from the groupconsisting of:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb IV, IVa, IVb, V, Va, or Vb is:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is:

In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is:

III. Compositions and Kits

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are alsopharmaceutical compositions that comprise one or more of the compoundsprovided herein or pharmaceutically acceptable salts, isomer, or amixture thereof and one or more pharmaceutically acceptable vehiclesselected from carriers, adjuvants and excipients. The compounds providedherein may be the sole active ingredient or one of the activeingredients of the pharmaceutical compositions. Suitablepharmaceutically acceptable vehicles may include, for example, inertsolid diluents and fillers, diluents, including sterile aqueous solutionand various organic solvents, permeation enhancers, solubilizers andadjuvants. Such compositions are prepared in a manner well known in thepharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, MacePublishing Co., Philadelphia, Pa. 17th Ed. (1985); and ModernPharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes,Eds.).

In one aspect, provided herein are pharmaceutical compositionscomprising a compound provided herein (e.g., a compound of Formula I,Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient or carrier. In some embodiments, the pharmaceuticalcompositions comprise a therapeutically effective amount of a compoundprovided herein, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient or carrier.

In some embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more (e.g., one, two, three, four, one or two,one to three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical compositions further comprise a therapeutically effectiveamount of the one or more (e.g., one, two, three, four, one or two, oneto three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof.

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical compositions may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In some embodiments, the pharmaceutical compositionsmay be administered by intra-arterial injection, intravenously,intraperitoneally, parenterally, intramuscularly, subcutaneously,orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds provided herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound provided herein orpharmaceutically acceptable salts, isomer, or a mixture thereof, theactive ingredient (such as a compound provided herein) is usuallydiluted by an excipient and/or enclosed within such a carrier that canbe in the form of a capsule, sachet, paper or other container. When theexcipient serves as a diluent, it can be in the form of a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the pharmaceutical compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols(as a solid or in a liquid medium), ointments containing, for example,up to 10% by weight of the active compound, soft and hard gelatincapsules, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose or any combinations thereof. The pharmaceutical compositionscan additionally include lubricating agents such as talc, magnesiumstearate, and mineral oil; wetting agents; emulsifying and suspendingagents; preserving agents such as methyl and propylhydroxy-benzoates;sweetening agents; and flavoring agents; or any combinations thereof.

The pharmaceutical compositions that include at least one compounddescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof can be formulated so as to provide quick, sustained ordelayed release of the active ingredient (such as a compound providedherein) after administration to the subject by employing proceduresknown in the art. Controlled release drug delivery systems for oraladministration include osmotic pump systems and dissolution systemscontaining polymer-coated reservoirs or drug-polymer matrixformulations. Examples of controlled release systems are given in U.S.Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Anotherformulation for use in the methods of the present disclosure employstransdermal delivery devices (“patches”). Such transdermal patches maybe used to provide continuous or discontinuous infusion of the compoundsprovided herein in controlled amounts. The construction and use oftransdermal patches for the delivery of pharmaceutical agents is wellknown in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and5,001,139. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof. When referring to these preformulationcompositions as homogeneous, the active ingredient may be dispersedevenly throughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with materials such as shellac, cetyl alcohol, andcellulose acetate.

Pharmaceutical compositions for inhalation or insufflation may includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof, and powders. The liquid or solidcompositions may contain suitable pharmaceutically acceptable excipientsas described supra. In some embodiments, the compositions areadministered by the oral or nasal respiratory route for local orsystemic effect. In other embodiments, compositions in pharmaceuticallyacceptable solvents may be nebulized by use of inert gases. Nebulizedsolutions may be inhaled directly from the nebulizing device or thenebulizing device may be attached to a facemask tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions may be administered, preferably orally or nasally, fromdevices that deliver the formulation in an appropriate manner.

In one aspect, provided herein are kits that comprise a compoundprovided herein, (e.g., a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb), or a pharmaceuticallyacceptable salt, stereoisomer, prodrug, or solvate thereof, and suitablepackaging. In some embodiments, the kit further comprises instructionsfor use. In some embodiments, the kit comprises a compound providedherein (e.g., a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa,IIIb, IV, IVa, IVb, V, Va, or Vb), or a pharmaceutically acceptablesalt, stereoisomer, prodrug, or solvate thereof, and a label and/orinstructions for use of the compounds in the treatment of theindications, including the diseases or conditions, described herein.

In some embodiments, the kits further comprise one or more (e.g., one,two, three, four, one or two, one to three, or one to four) additionaltherapeutic agents, or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are articles of manufacture that comprisea compound described herein or pharmaceutically acceptable salts,isomer, or a mixture thereof in a suitable container. In someembodiments, the container may be a vial, jar, ampoule, preloadedsyringe, or intravenous bag.

IV. Methods

In one embodiment, methods of treating an HIV (e.g., HIV-1 and/or HIV-2)infection in a human having or at risk of having the infectioncomprising administering to the human a therapeutically effective amountof a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV,IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition of a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or apharmaceutically acceptable salt thereof, are provided.

In some embodiments, the methods further comprise administering to thehuman a therapeutically effective amount of one, two, three, or fouradditional therapeutic agents. In certain embodiments, the additionaltherapeutic agent or agents are anti-HIV agents. In particularembodiments, the additional therapeutic agent or agents are HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors,gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsidpolymerization inhibitors, HIV bNAbs (broadly neutralizing HIVantibodies), TLR7 agonists, pharmacokinetic enhancers, other drugs fortreating HIV, or combinations thereof. In one embodiment, the additionaltherapeutic agent or agents are abacavir, tenofovir alafenamide,tenofovir disoproxil, lenacapavir, or a pharmaceutically acceptable saltthereof. In one embodiment, the additional therapeutic agent or agentsare abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir,GS-5894, islatravir, or a pharmaceutically acceptable salt thereof. Insome embodiments, the additional therapeutic agent or agents arelenacapavir, islatravir. In some embodiments, the additional therapeuticagent is lenacapavir. In some embodiments, the additional therapeuticagent is islatravir.

In another embodiment, a use of a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa,IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable saltthereof, for treating an HIV (e.g., HIV-1 and/or HIV-2) infection in ahuman having or at risk of having the infection is provided.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of a compoundof Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V,Va, or Vb, or a pharmaceutically acceptable salt thereof, for use inmedical therapy is provided.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of Formula I,Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, orpharmaceutically acceptable salt thereof, for use in treating an HIVinfection is provided.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of a compoundof Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V,Va, or Vb, or a pharmaceutically acceptable salt thereof for use in amethod of treating an HIV infection in a human having or at risk ofhaving the infection, is provided.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of a compoundof Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V,Va, or Vb, or a pharmaceutically acceptable salt thereof for use in amethod of treating an HIV infection in a human having or at risk ofhaving the infection, is provided wherein said method further comprisesadministering to the human one, two, three, or four additionaltherapeutic agents.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of a compoundof Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V,Va, or Vb, or a pharmaceutically acceptable salt thereof for use in amethod of treating an HIV infection in a human having or at risk ofhaving the infection, is provided wherein said method further comprisesadministering to the human one, two, three, or four additionaltherapeutic agents selected from the group consisting of HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors,gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsidpolymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokineticenhancers, other drugs for treating HIV, or combinations thereof. In oneembodiment, the one, two, three, or four additional therapeutic agentsare selected from HIV protease inhibitors, HIV non-nucleoside inhibitorsof reverse transcriptase, HIV nucleoside or nucleotide inhibitors ofreverse transcriptase, latency reversing agents, HIV capsid inhibitors,HIV bNAbs, TLR7 agonists, and combinations thereof.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of a compoundof Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V,Va, or Vb, or a pharmaceutically acceptable salt thereof for use in amethod of treating an HIV infection in a human having or at risk ofhaving the infection, is provided wherein said method further comprisesadministering to the human a therapeutically effective amount oftenofovir disoproxil and emtricitabine.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of a compoundof Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V,Va, or Vb, or a pharmaceutically acceptable salt thereof for use in amethod of treating an HIV infection in a human having or at risk ofhaving the infection, is provided wherein said method further comprisesadministering to the human a therapeutically effective amount oftenofovir alafenamide and emtricitabine.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of a compoundof Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V,Va, or Vb, or a pharmaceutically acceptable salt thereof for use in amethod of treating an HIV infection in a human having or at risk ofhaving the infection, is provided wherein said method further comprisesadministering to the human a therapeutically effective amount oftenofovir disoproxil.

In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of a compoundof Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V,Va, or Vb, or a pharmaceutically acceptable salt thereof for use in amethod of treating an HIV infection in a human having or at risk ofhaving the infection, is provided wherein said method further comprisesadministering to the human a therapeutically effective amount oftenofovir alafenamide.

In another embodiment, a method of using a compound of Formula I, Ia,Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb in therapyis provided. In particular, a method of treating the proliferation ofthe HIV virus, treating AIDS, or delaying the onset of AIDS or ARCsymptoms in a mammal (e.g., a human) is provided, comprisingadministering to the mammal a compound of Formula I, Ia, Ib, II, IIa,IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In another embodiment, a composition comprising a compound of Formula I,Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient, for use in a method of treating the proliferationof the HIV virus, treating AIDS, or delaying the onset of AIDS or ARCsymptoms in a mammal (e.g., a human) is provided.

In one embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb, III,IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition of a compound of FormulaI, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, ora pharmaceutically acceptable salt thereof, is provided for use inpreventing HIV infection.

For example, in one embodiment, a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa,IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable saltthereof, is provided for use in pre-exposure prophylaxis (PrEP), i.e.,before the exposure of the individual to the HIV virus to prevent HIVinfection from taking hold if the individual is exposed to the virusand/or to keep the virus from establishing a permanent infection and/orto prevent the appearance of symptoms of the disease and/or to preventthe virus from reaching detectable levels in the blood.

In another embodiment, the use of a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating an HIV infection in a human being having or atrisk of having the infection is disclosed.

In another embodiment, the use of a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or apharmaceutically acceptable salt thereof, as a research tool isdisclosed.

In another embodiment, an article of manufacture comprising acomposition effective to treat an HIV infection; and packaging materialcomprising a label which indicates that the composition can be used totreat infection by HIV is disclosed. Exemplary compositions comprise acompound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa,IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof.

In still another embodiment, a method of inhibiting the replication ofHIV is disclosed. The method comprises exposing the virus to aneffective amount of the compound of Formula I, Ia, Ib, II, IIa, IIb,III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a salt thereof, underconditions where replication of HIV is inhibited.

In another embodiment, the use of a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, to inhibit theactivity of the HIV integrase enzyme is disclosed.

In another embodiment, the use of a compound of Formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a saltthereof, to inhibit the replication of HIV is disclosed.

V. Administration

The compounds of the present disclosure (also referred to herein as theactive ingredients), can be administered by any route appropriate to thecondition to be treated. Suitable routes include oral, rectal, nasal,topical (including buccal and sublingual), transdermal, vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural), and the like. It will beappreciated that the preferred route may vary with, for example, thecondition of the recipient. An advantage of certain compounds disclosedherein is that they are orally bioavailable and can be dosed orally.

A compound of the present disclosure may be administered to anindividual in accordance with an effective dosing regimen for a desiredperiod of time or duration, such as at least about one month, at leastabout 2 months, at least about 3 months, at least about 6 months, or atleast about 12 months or longer. In some embodiments, the compound isadministered on a daily or intermittent schedule for the duration of theindividual's life.

The specific dose level of a compound of the present disclosure for anyparticular subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound described herein per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate.In some embodiments, about 0.1 and 100 mg/kg may be appropriate. Inother embodiments a dosage of between 0.5 and 60 mg/kg may beappropriate. Normalizing according to the subject's body weight isparticularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compounddescribed herein administered per dose or per day. Daily dosage of acompound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa,IVb, V, Va, or Vb, or a pharmaceutically acceptable salt orpharmaceutically acceptable tautomer thereof, may be between about 1 mgand 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day,between about 75 to 200 mg/day, or between about 15 to 150 mg/day.

The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgmentof the administering physician.

The compounds of the present disclosure may be administered to anindividual (e.g., a human) in a therapeutically effective amount. Insome embodiments, the compound is administered once daily.

The compounds provided herein can be administered by any useful routeand means, such as by oral or parenteral (e.g., intravenous)administration. Therapeutically effective amounts of the compound mayinclude from about 0.00001 mg/kg body weight per day to about 10 mg/kgbody weight per day, such as from about 0.0001 mg/kg body weight per dayto about 10 mg/kg body weight per day, or such as from about 0.001 mg/kgbody weight per day to about 1 mg/kg body weight per day, or such asfrom about 0.01 mg/kg body weight per day to about 1 mg/kg body weightper day, or such as from about 0.05 mg/kg body weight per day to about0.5 mg/kg body weight per day. In some embodiments, a therapeuticallyeffective amount of the compounds provided herein include from about 0.3mg to about 30 mg per day, or from about 30 mg to about 300 mg per day,or from about 0.3 μg to about 30 mg per day, or from about 30 μg toabout 300 μg per day.

A compound of the present disclosure may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound ofthe present disclosure (e.g., from 1 mg to 1000 mg of compound).Therapeutically effective amounts may include from about 0.1 mg per doseto about 1000 mg per dose, such as from about 50 mg per dose to about500 mg per dose, or such as from about 100 mg per dose to about 400 mgper dose, or such as from about 150 mg per dose to about 350 mg perdose, or such as from about 200 mg per dose to about 300 mg per dose, orsuch as from about 0.01 mg per dose to about 1000 mg per dose, or suchas from about 0.01 mg per dose to about 100 mg per dose, or such as fromabout 0.1 mg per dose to about 100 mg per dose, or such as from about 1mg per dose to about 100 mg per dose, or such as from about 1 mg perdose to about 10 mg per dose, or such as from about 1 mg per dose toabout 1000 mg per dose. Other therapeutically effective amounts of thecompound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa,IVb, V, Va, or Vb are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8,9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,95, or about 100 mg per dose. Other therapeutically effective amounts ofthe compound of the present disclosure are about 100, 125, 150, 175,200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525,550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875,900, 925, 950, 975, or about 1000 mg per dose.

In some embodiments, the methods described herein comprise administeringto the subject an initial daily dose of about 1 to 500 mg of a compoundp herein and increasing the dose by increments until clinical efficacyis achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used toincrease the dose. The dosage can be increased daily, every other day,twice per week, once per week, once every two weeks, once every threeweeks, or once a month.

When administered orally, the total daily dosage for a human subject maybe between about 1 mg and 1,000 mg, between about 10-500 mg/day, betweenabout 50-300 mg/day, between about 75-200 mg/day, or between about100-150 mg/day. In some embodiments, the total daily dosage for a humansubject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or1000 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 200, 300, 400, 500,600, 700, or 800 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about300, 400, 500, or 600 mg/day administered in a single dose.

In some embodiments, the total daily dosage for a human subject may beabout 100 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 150 mg/dayadministered in a single dose. In some embodiments, the total dailydosage for a human subject may be about 200 mg/day administered in asingle dose. In some embodiments, the total daily dosage for a humansubject may be about 250 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 300mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 350 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 400 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 450mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 500 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 550 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 600mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 650 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 700 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 750mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 800 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 850 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 900mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 950 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 1000 mg/day administered in a single dose.

A single dose can be administered hourly, daily, weekly, or monthly. Forexample, a single dose can be administered once every 1 hour, 2, 3, 4,6, 8, 12, 16 or once every 24 hours. A single dose can also beadministered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. Asingle dose can also be administered once every 1 week, 2, 3, or onceevery 4 weeks. In certain embodiments, a single dose can be administeredonce every week. A single dose can also be administered once everymonth. In some embodiments, a compound disclosed herein is administeredonce daily in a method disclosed herein. In some embodiments, a compounddisclosed herein is administered twice daily in a method disclosedherein.

In some embodiments, a compound disclosed herein is administered onceevery 10 days. In some embodiments, a compound disclosed herein isadministered once every 15 days. In some embodiments, a compounddisclosed herein is administered once every 20 days. In someembodiments, a compound disclosed herein is administered once every10-15 days. In some embodiments, a compound disclosed herein isadministered once every 15-20 days. In some embodiments, a compounddisclosed herein is administered once every 10-20 days. In someembodiments, a compound disclosed herein is administered once everymonth. In some embodiments, a compound disclosed herein is administeredonce every 2 months. In some embodiments, a compound disclosed herein isadministered once every 3 months. In some embodiments, a compounddisclosed herein is administered once every 4 months. In someembodiments, a compound disclosed herein is administered once every 5months. In some embodiments, a compound disclosed herein is administeredonce every 6 months. In some embodiments, a compound disclosed herein isadministered once every 8 months. In some embodiments, a compounddisclosed herein is administered once every 10 months. In someembodiments, a compound disclosed herein is administered once everyyear.

The frequency of dosage of the compound of the present disclosure willbe determined by the needs of the individual patient and can be, forexample, once per day or twice, or more times, per day. Administrationof the compound continues for as long as necessary to treat the HBVinfection, HIV infection, cancer, hyper-proliferative disease, or anyother indication described herein. For example, a compound can beadministered to a human being infected with HBV for a period of from 20days to 180 days or, for example, for a period of from 20 days to 90days or, for example, for a period of from 30 days to 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of the compound of thepresent disclosure followed by a period of several or more days duringwhich a patient does not receive a daily dose of the compound. Forexample, a patient can receive a dose of the compound every other day,or three times per week. Again by way of example, a patient can receivea dose of the compound each day for a period of from 1 to 14 days,followed by a period of 7 to 21 days during which the patient does notreceive a dose of the compound, followed by a subsequent period (e.g.,from 1 to 14 days) during which the patient again receives a daily doseof the compound. Alternating periods of administration of the compound,followed by non-administration of the compound, can be repeated asclinically required to treat the patient.

The compounds of the present disclosure or the pharmaceuticalcompositions thereof may be administered once, twice, three, or fourtimes daily, using any suitable mode described above. Also,administration or treatment with the compounds may be continued for anumber of days; for example, commonly treatment would continue for atleast 7 days, 14 days, or 28 days, for one cycle of treatment. Treatmentcycles are well known in cancer chemotherapy, and are frequentlyalternated with resting periods of about 1 to 28 days, commonly about 7days or about 14 days, between cycles. The treatment cycles, in otherembodiments, may also be continuous.

VI. Combination Therapy

In certain embodiments, a method for treating or preventing an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, one or two, or one tothree) additional therapeutic agents. In one embodiment, a method fortreating an HIV infection in a human having or at risk of having theinfection is provided, comprising administering to the human atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents.

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more (e.g., one, two, three, one or two, or oneto three) additional therapeutic agents, and a pharmaceuticallyacceptable carrier, diluent, or excipient are provided.

In certain embodiments, the present disclosure provides a method fortreating an HIV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents which are suitable for treating an HIV infection.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four, or more additional therapeutic agents. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four, or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

Administration of HIV Combination Therapy

In certain embodiments, a compound disclosed herein is administered withone or more additional therapeutic agents. Co-administration of acompound disclosed herein with one or more additional therapeutic agentsgenerally refers to simultaneous or sequential administration of acompound disclosed herein and one or more additional therapeutic agents,such that therapeutically effective amounts of the compound disclosedherein and the one or more additional therapeutic agents are bothpresent in the body of the patient. When administered sequentially, thecombination may be administered in two or more administrations.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents. For example, thecompound disclosed herein may be administered within seconds, minutes,or hours of the administration of the one or more additional therapeuticagents. In some embodiments, a unit dose of a compound disclosed hereinis administered first, followed within seconds or minutes byadministration of a unit dose of one or more additional therapeuticagents. Alternatively, a unit dose of one or more additional therapeuticagents is administered first, followed by administration of a unit doseof a compound disclosed herein within seconds or minutes. In otherembodiments, a unit dose of a compound disclosed herein is administeredfirst, followed, after a period of hours (e.g., 1-12 hours), byadministration of a unit dose of one or more additional therapeuticagents. In yet other embodiments, a unit dose of one or more additionaltherapeutic agents is administered first, followed, after a period ofhours (e.g., 1-12 hours), by administration of a unit dose of a compounddisclosed herein.

In certain embodiments, a compound disclosed herein is combined with oneor more additional therapeutic agents in a unitary dosage form forsimultaneous administration to a patient, for example as a solid dosageform for oral administration.

In certain embodiments, a compound of Formula I is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HIV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HIV, such as HIV protease inhibitors, HIVnon-nucleoside or non-nucleotide inhibitors of reverse transcriptase,HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, HIV non-catalytic site (or allosteric) integraseinhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

HIV Combination Therapy

In the above embodiments, the additional therapeutic agent may be ananti-HIV agent. HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, immunomodulators,immunotherapeutic agents, antibody-drug conjugates, gene modifiers, geneeditors (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases,synthetic nucleases, TALENs), cell therapies (such as chimeric antigenreceptor T-cell, CAR-T, and engineered T cell receptors, TCR-T,autologous T cell therapies), latency reversing agents, compounds thattarget the HIV capsid, immune-based therapies, phosphatidylinositol3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors,IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators,protein disulfide isomerase inhibitors, complement C5a receptorantagonists, DNA methyltransferase inhibitor, HIV vif gene modulators,Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors,TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinasemodulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicinginhibitors, Rev protein inhibitors, integrin antagonists, nucleoproteininhibitors, splicing factor modulators, COMM domain containing protein 1modulators, CD4 modulators, CD4 antagonists, HIV ribonuclease Hinhibitors, retrocyclin modulators, CDK-9 inhibitors, CCR5 chemokineantagonists, CCR5 gene modulators, dendritic ICAM-3 grabbing nonintegrin1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors,hyaluronidase inhibitors, Nef antagonists, Nef inhibitors,Protease-activated receptor-1 antagonists, TNF alpha ligand inhibitors,PDE4 inhibitors, Complement Factor H modulators, ubiquitin ligaseinhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinaseinhibitors, proprotein convertase PC9 stimulators, ATP dependent RNAhelicase DDX3X inhibitors, reverse transcriptase priming complexinhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers,HIV gene therapy, HIV vaccines, and combinations thereof.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of combination drugs for HIV, other drugs fortreating HIV, HIV protease inhibitors, HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIVmaturation inhibitors, latency reversing agents, capsid inhibitors,immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecificantibodies, and “antibody-like” therapeutic proteins, and combinationsthereof.

HIV Combination Drugs

Examples of combination drugs include ATRIPLA® (efavirenz, tenofovirdisoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir,emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®;rilpivirine, tenofovir disoproxil fumarate, and emtricitabine);STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, andemtricitabine); TRUVADA® (tenofovir disoproxil fumarate andemtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide andemtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofoviralafenamide hemifumarate, emtricitabine, and cobicistat); SYMFI™(efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU™(lamivudine and tenofovir disoproxil fumarate); tenofovir andlamivudine; tenofovir alafenamide and emtricitabine; tenofoviralafenamide hemifumarate and emtricitabine; tenofovir alafenamidehemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamidehemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR®(zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavirsulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir andritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR®(abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavirand cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfateand ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine;dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavirsulfate, and lamivudine; lamivudine, nevirapine, and zidovudine;raltegravir and lamivudine; doravirine, lamivudine, and tenofovirdisoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil;dapivirine+levonorgestrel, dolutegravir+lamivudine,dolutegravir+emtricitabine+tenofovir alafenamide,elsulfavirine+emtricitabine+tenofovir disoproxil,lamivudine+abacavir+zidovudine, lamivudine+abacavir,lamivudine+tenofovir disoproxil fumarate,lamivudine+zidovudine+nevirapine, lopinavir+ritonavir,lopinavir+ritonavir+abacavir+lamivudine,lopinavir+ritonavir+zidovudine+lamivudine, tenofovir+lamivudine, andtenofovir disoproxil fumarate+emtricitabine+rilpivirine hydrochloride,lopinavir, ritonavir, zidovudine and lamivudine.

Other HIV Drugs

Examples of other drugs for treating HIV include acemannan, alisporivir,astodrimer, BanLec, CC-11050, deferiprone, Gamimune, griffithsin,metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, Vorapaxar, VSSP,HIviral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazFgene therapy, MK-8527, BlockAide, PSC-RANTES, ABX-464, AG-1105,APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100,IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040(PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110,TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

HIV Protease Inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir,brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir,indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate,ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657(PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911.

HIV Reverse Transcriptase Inhibitors

Examples of HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase include dapivirine, delavirdine, delavirdine mesylate,doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine,rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, andelsulfavirine (VM-1500).

Examples of HIV nucleoside or nucleotide inhibitors of reversetranscriptase include adefovir, adefovir dipivoxil, azvudine,emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine,apricitabine, censavudine, didanosine, elvucitabine, festinavir,fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine,OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir,lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafoviretalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500 andKP-1461.

HIV Integrase Inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin,derivatives of curcumin, chicoric acid, derivatives of chicoric acid,3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid,aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeicacid phenethyl ester, derivatives of caffeic acid phenethyl ester,tyrphostin, derivatives of tyrphostin, quercetin, derivatives ofquercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567,BMS-986197, cabotegravir (long-acting injectable), diketo quinolin-4-1derivatives, integrase-LEDGF inhibitor, ledgins, M-522, M-532,NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172,NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169, VM-3500 andcabotegravir.

Examples of HIV non-catalytic site, or allosteric, integrase inhibitors(NCINI) include CX-05045, CX-05168, and CX-14442.

HIV Entry Inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003(BMS-599793), gp120 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc,cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc(TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66,polypeptide C25P, TD-0680, and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide,BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusioninhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer andsifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADAanalogs.

Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38,BanLec, bentonite-based nanomedicine, fostemsavir tromethamine,IQP-0831, and BMS-663068.

Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide,and vMIP (Haimipu).

HIV Maturation Inhibitors

Examples of HIV maturation inhibitors include BMS-955176, BMS-986197,GSK-3640254 and GSK-2838232.

Latency Reversing Agents

Examples of latency reversing agents include histone deacetylase (HDAC)inhibitors, proteasome inhibitors such as velcade, and ixazomib citrate,protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4(BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid, orsuberoyl, anilide, and hydroxamic acid), IL-15 modulating antibodies,JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such aslargazole analogs, APH-0812, and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat, andpanobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B,and DAG-lactones.

Capsid Inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitorsor capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitorssuch as azodicarbonamide, HIV p24 capsid protein inhibitors, GS-6207,AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series.

Immune-Based Therapies

Examples of immune-based therapies include toll-like receptorsmodulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9,tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1)modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine);proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b;interferon alfa-n3; pegylated interferon alfa; interferon gamma;hydroxyurea; mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (PEI);gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107,interleukin-15/Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255,NKTR-262, NKTR-214, normferon, peginterferon alfa-2a, peginterferonalfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STINGmodulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103.

Examples of TLR agonists: vesatolimod (GS-9620), GS-986, IR-103,lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100,cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463,GS-9688, LHC-165, BDB-001, RG-7854, telratolimod.RO-7020531.

Phosphatidylinositol 3-kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib,CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib,perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib,rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439,CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577,GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666,RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857,VS-5584, XL-765, and ZSTK-474.

Alpha-4 Beta-7 Antagonists

Examples of Integrin alpha-4/beta-7 antagonists include PTG-100,TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV Antibodies, Bispecific Antibodies, and “Antibody-Like” TherapeuticProteins

Examples of HIV antibodies, bispecific antibodies, and “antibody-like”therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®,TandAbs®, Fab derivatives, bispecific antibodies, trispecificantibodies, multivalent antibodies, bnABs (broadly neutralizing HIV-1antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41,antibody-recruiting Molecules targeting HIV, anti-CD63 monoclonalantibodies, CD3 bispecific antibodies, CD16 bispecific antibodies,anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies,anti-Nef single domain antibodies, anti-Rev antibody, camelid derivedanti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001,gp140 targeted antibodies, gp41-based HIV therapeutic antibodies, humanrecombinant mAbs (PGT-121), ibalizumab, Immuglo, MB-66.

Examples of those targeting HIV in such a manner include bavituximab,UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117,3BNC117-LS, 3BNC60, D1D2, 10-1074, 10-1074-LS, GS-9722, DH411-2, BG18,PGT145, PGT121, PGT122, PGT-151, PGT-133, PGT-135, PGT-128, MDX010(ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9,N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PG9,PG16, 8ANC195, 2Dm2m, 4Dm2m, 6Dm2m, VRC-01, VRC-01-LS, PGDM1400, A32,7B2, 10E8, 10E8VLS, 3810109, 10E8v4, 10E8.4/iMab,VRC-01/PGDM-1400/10E8v4, IMC-HIV, iMabm36, 10E8v4/PGT121-VRC01, eCD4-Ig,IOMA, CAP256-VRC26.25, DRVIA7, SAR-441236, VRC-07-523, VRC₀₇₋₅₂3LS,VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, and VRC07. Examples ofHIV bispecific antibodies include MGD014, TMB-bispecific.

Example of in vivo delivered bnABs such as AAV8-VRC07; mRNA encodinganti-HIV antibody VRCO1.

Pharmacokinetic Enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

Additional Therapeutic Agents

Examples of additional therapeutic agents include the compoundsdisclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (GileadSciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (GileadSciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (GileadSciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (GileadSciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (Universityof Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380(Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO2013/091096 (Boehringer Ingelheim).

HIV Vaccines

Examples of HIV vaccines include peptide vaccines, recombinant subunitprotein vaccines, live vector vaccines using viral vectors such asarenavirus, lymphocytic choriomeningitis virus (LCMV), pichinde virus,modified vaccinia Ankara virus (MVA), adenovirus, adeno-associated virus(AAV), vesicular stomatitis virus (VSV) and Chimpanzee adenovirus(ChAd), DNA vaccines, CD4-derived peptide vaccines, vaccinecombinations, BG505 SOSIP.664 gp140, rgp120 (AIDSVAX), ALVAC HIV,(vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype Cvaccine, Remune, ITV-1, Contre Vir, Ad4-Env145NFL, Ad5-ENVA-48, HB-500,DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, Vacc-CRX, VVX-004, VAC-3S,multiclade DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A/B/Cvaccine, Pennvax-G, Pennvax-GP/MVA-CMDR, HIV-TriMix-mRNA vaccine,HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvantedvaccines, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59,rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV,TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123,rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env CladeC+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101,CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env,Ad26.Mod.HIV vaccine, Ad26.Mod.HIV+MVA mosaic vaccine+gp140, AGS-004,AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300,IHV-001, and virus-like particle vaccines such as pseudovirion vaccine,CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, HIVgag/pol/nef/env DNA vaccine, anti-TAT HIV vaccine, conjugatepolypeptides vaccine, dendritic-cell vaccines, gag-based DNA vaccine,GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i-key/MHCclass II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5,multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMVvector HIV gag vaccine, recombinant peptide vaccine (HIV infection),NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine,TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+romidepsin,variant gp120 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine,DNA.HTI, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP,INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer based vaccine,PD-201401, env (A, B, C, A/E)/gag (C) DNA Vaccine, gp120 (A,B,C,A/E)protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine(GLA-SE adjuvanted), HIV p24gag prime-boost plasmid DNA vaccine,arenavirus vector-based immunotherapies (Vaxwave, TheraT), MVA-BN HIV-1vaccine regimen, MVA.tHIVconsv4, MVA.tHIVconsv3, UBI HIV gp120, mRNAbased prophylactic vaccines, TBL-1203HI, VRC-HIVRGP096-00-VP, VAX-3S,HIV MAG DNA vaccine,

HIV Combination Therapy

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from ATRIPLA®(efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA®(EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, andemtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovirdisoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxilfumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamideand emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat;emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxilfumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate;TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir,abacavir sulfate, and lamivudine; raltegravir; raltegravir andlamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir andritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavirsulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine;rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavirand cobicistat; darunavir and cobicistat; atazanavir; atazanavirsulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate andritonavir; darunavir; lamivudine; prolastin; fosamprenavir;fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavirmesylate; interferon; didanosine; stavudine; indinavir; indinavirsulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir;saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir;delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine andtenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine;abacavir; and abacavir sulfate.

It will be appreciated by one of skill in the art that the additionaltherapeutic agents listed above may be included in more than one of theclasses listed above. The particular classes are not intended to limitthe functionality of those compounds listed in those classes.

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase and an HIVnon-nucleoside inhibitor of reverse transcriptase. In another specificembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, and an HIV proteaseinhibiting compound. In an additional embodiment, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withan HIV nucleoside or nucleotide inhibitor of reverse transcriptase, anHIV non-nucleoside inhibitor of reverse transcriptase, and apharmacokinetic enhancer. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withat least one HIV nucleoside inhibitor of reverse transcriptase, anintegrase inhibitor, and a pharmacokinetic enhancer. In anotherembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two HIV nucleoside ornucleotide inhibitors of reverse transcriptase.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofoviralafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide, or tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofabacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxilfumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate,and a second additional therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting oftenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and asecond additional therapeutic agent, wherein the second additionaltherapeutic agent is emtricitabine.

A compound as disclosed herein (e.g., any compound of Formula I) may becombined with one or more additional therapeutic agents in any dosageamount of the compound of Formula I (e.g., from 1 mg to 500 mg ofcompound).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30,or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 10 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide,and 200 mg emtricitabine. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with25 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Acompound as disclosed herein (e.g., a compound of Formula I) may becombined with the agents provided herein in any dosage amount of thecompound (e.g., from 1 mg to 500 mg of compound) the same as if eachcombination of dosages were specifically and individually listed.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 200-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400,350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil, and 200 mgemtricitabine. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 300 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. A compound as disclosedherein (e.g., a compound of Formula I) may be combined with the agentsprovided herein in any dosage amount of the compound (e.g., from 1 mg to500 mg of compound) the same as if each combination of dosages werespecifically and individually listed.

In one embodiment, kits comprising a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with one ormore (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents are provided.

Birth Control (Contraceptive) Combination Therapy

Therapeutic agents used for birth control (contraceptive) includecyproterone acetate, desogestrel, dienogest, drospirenone, estradiolvalerate, ethinyl Estradiol, ethynodiol, etonogestrel, levomefolate,levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol,mifepristone, misoprostol, nomegestrol acetate, norelgestromin,norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersoneacetate, ulipristal acetate, and any combinations thereof.

Gene Therapy and Cell Therapy

Gene Therapy and Cell Therapy including the genetic modification tosilence a gene; genetic approaches to directly kill the infected cells;the infusion of immune cells designed to replace most of the patient'sown immune system to enhance the immune response to infected cells, oractivate the patient's own immune system to kill infected cells, or findand kill the infected cells; genetic approaches to modify cellularactivity to further alter endogenous immune responsiveness against theinfection.

Examples of dendritic cell therapy include AGS-004.

Example of CCR5 gene editing drugs such as SB-728T.

Example of CCR5 gene inhibitors such as Cal-1.

C34-CCR5/C34-CXCR4 expressing CD4-positive T cells.

AGT-103-transduced autologous T cell therapy.

AAV-eCD4-Ig gene therapy.

Gene Editors

The genome editing system is selected from the group consisting of: aCRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, ahoming endonucleases system, and a meganuclease system.

Examples of HIV targeting CRISPR/Cas9 systems include EBT-101.

CAR-T Cell Therapy

A population of immune effector cells engineered to express a chimericantigen receptor (CAR), wherein the CAR comprises an HIV antigen-bindingdomain. The HIV antigen include an HIV envelope protein or a portionthereof, gp120 or a portion thereof, a CD4 binding site on gp120, theCD4-induced binding site on gp120, N glycan on gp120, the V2 of gp120,the membrane proximal region on gp41. The immune effector cell is a Tcell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, aCD8+ T cell, or a combination thereof. Cells can be autologous orallogeneic.

Examples of HIV CAR-T include VC-CAR-T, anti-CD4 CART cell therapy,autologous hematopoietic stem cells genetically engineered to express aCD4 CAR and the C46 peptide.

TCR-T Cell Therapy

TCR-T cells are engineered to target HIV derived peptides present on thesurface of virus-infected cells.

VII. Examples

Exemplary chemical entities of the present disclosure are provided inthe specific examples that follow. Those skilled in the art willrecognize that, to obtain the various compounds herein, startingmaterials may be suitably selected so that the ultimately desiredsubstituents will be carried through the reaction scheme with or withoutprotection as appropriate to yield the desired product. Alternatively,it may be necessary or desirable to employ, in the place of theultimately desired substituent, a suitable group that may be carriedthrough the reaction scheme and replaced as appropriate with the desiredsubstituent. Furthermore, one of skill in the art will recognize thatthe transformations shown in the schemes below may be performed in anyorder that is compatible with the functionality of the particularpendant groups.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

In the following description of the Examples, specific embodiments aredescribed. These embodiments are described in sufficient detail toenable those skilled in the art to practice certain embodiments of thepresent disclosure. Other embodiments may be utilized and logical andother changes may be made without departing from the scope of thedisclosure. The following description is, therefore, not intended tolimit the scope of the present disclosure.

Example 1-4: Preparation of(6R)-10-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C1)(6R)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C2)(6S)-10-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C3)(6S)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C4)

5-(Benzyloxy)-2,3-dihydro-1H-pyrido[2,1-f][1,2,4]triazine-4,6-dione (1)was prepared according to published procedure for “intermediate A” in WO20191160883 A1.

Step 1: Preparation of1-(benzyloxy)-10-fluoro-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(2-a) and1-(benzyloxy)-9-fluoro-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(2-b)

5-(Benzyloxy)-2,3-dihydro-1H-pyrido[2,1-f][1,2,4]triazine-4,6-dione (1)(200 mg, 0.737 mmol) and 1,2-bis(bromomethyl)-4-fluorobenzene (229 mg,0.811 mmol) were mixed with DMF (5 ml) and the mixture was cooled downto 0° C. NaOt-Bu (159 mg, 1.66 mmol) was added over 1 hr. The reactionmixture was the allowed to be stirred without recharged cold bathovernight. The reaction mixture was then diluted with EtOAc and wastreated with NH₄Cl/water. Organic phase was separated and concentrated.The residue was purified with silica gel chromatography with 0-100%EtOAc in Heptane and then 10% MeOH in EtOAc to afford the mixture of tworegio-isomers of products (2-a and 2-b). MS (m/z): 392.1 [M+H]. Thesetwo regio-isomers were not separated and were carried over to next step.

Step 2: Preparation of1-(benzyloxy)-10-fluoro-3-iodo-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(3-a) and1-(benzyloxy)-9-fluoro-3-iodo-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(3-b)

A mixture of1-(benzyloxy)-10-fluoro-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(2-a) and1-(benzyloxy)-9-fluoro-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(2-b) (50 mg, 0.128 mmol) was mixed with MeOH (0.8 ml) at rt. m-CPBA(77%) (114 mg, 0.51 mmol) and NIS (114 mg, 0.51 mmol) were addedsequentially. Reaction vial was sealed and heated from rt to 80° C. for30 min. Additional m-CPBA (77%) (114 mg, 0.51 mmol) and NIS (114 mg,0.51 mmol) were added sequentially. Reaction mixture was heated again at80° C. for 30 min. Reaction mixture was then diluted with EtOAc andtreated with NaHCO₃/water and Na₂S₂O₃ (10%) in water. Organic phase wasseparated and concentrated. The residue was purified with silica gelcolumn with 0-100% EtOAc/Heptane to afford product as a mixture of tworegio-isomers (3-a and 3-b) 60 mg. MS (m/z): 518.06 [M+H]. These tworegio-isomers were not separated and carried over to next step.

Step 3: Preparation of:(6R)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-a)(6R)-1-(benzyloxy)-9-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-b)(6S)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-c)(6S)-1-(benzyloxy)-9-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-d)

To a solution of the mixture of1-(benzyloxy)-10-fluoro-3-iodo-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(3-a) and1-(benzyloxy)-9-fluoro-3-iodo-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(3-b) (32 mg, 0.062 mmol) in DMSO (2 ml) was added2,4,6-trifluorobenzylamine (50 mg, 0.309 mmol), DIPEA (40 mg, 0.309mmol), and Pd(PPh₃)₄ (3.57 mg, 0.00309 mmol). Reaction mixture wasbubbled with CO (g) for 10 min. The reaction mixture was then heated at80° C. under CO atmosphere for 17 hours. Reaction mixture was cooled toroom temperature and was diluted with ethyl acetate. The resultingmixture was treated with 0.05N HCl. Organic phase was separated and wastreated with saturated sodium bicarbonate solution and brine. Organicphase was then dried with Na₂SO₄ and was concentrated. The residue waspurified by silica gel column with 0-100% EtOAc in heptane to afforddesired product. This mixture of four isomers were subject to SFCseparation method (ADH 50 IPA-NH₃) to afford 4 isomers in the order ofascending retention time:(6R)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-a) 10 mg. MS (m/z): 579.08 [M+H];(6R)-1-(benzyloxy)-9-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-b) 6 mg. MS (m/z): 579.08 [M+H];(6S)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-c) 7 mg. MS (m/z): 579.03 [M+H]; and(6S)-1-(benzyloxy)-9-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-d) 4 mg. MS (m/z): 579.02 [M+H].

Step 4: Preparation of(6R)-10-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C1)

(6R)-1-(Benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-a) (10 mg, 0.0173 mmol) was dissolved in toluene (0.5 ml) at rt. TFA(0.5 ml) was added in one portion. Reaction mixture was stirred at rtfor 17 hrs. Reaction mixture was concentrated to dryness. The residuewas taken up in MeOH and purified with reverse phase prep-HPLC with0-100% CH₃CN in water with 0.1% TFA to afford the desired product.Lyophilization afforded the product as TFA salt. MS (m/z): 489.26[M+H]⁺. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.13 (s, 1H), 8.52 (s, 1H),7.41-7.22 (m, 1H), 7.13 (d, J=9.3 Hz, 1H), 7.04 (t, J=8.6 Hz, 1H), 6.88(t, J=8.6 Hz, 2H), 5.56 (d, J=16.7 Hz, 1H), 4.87-4.69 (m, 2H), 4.64 (d,J=5.7 Hz, 2H), 4.55 (d, J=15.3 Hz, 2H), 4.13 (d, J=13.2 Hz, 1H).

Preparation of(6R)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C2)

The synthesis of title product was taken in the same way as (C1) exceptusing(6R)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-b) as starting material instead of(6R)-1-(Benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-a). Product was obtained as TFA salt. MS (m/z): 489.14 [M+H]⁺. ¹H NMR(400 MHz, Acetonitrile-d3) δ 10.14 (s, 1H), 8.54 (d, J=17.3 Hz, 1H),7.36 (dd, J=8.4, 5.7 Hz, 1H), 7.23-6.98 (m, 2H), 6.88 (t, J=8.5 Hz, 2H),5.51 (d, J=16.5 Hz, 1H), 4.81 (p, J=14.7, 14.0 Hz, 2H), 4.64 (d, J=5.4Hz, 2H), 4.56 (dd, J=15.0, 10.4 Hz, 2H), 4.20 (d, J=13.6 Hz, 1H).

Preparation of(6S)-10-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C3)

The synthesis of title product was taken in the same way as (C1) exceptusing(6S)-10-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-c) as starting material instead of(6R)-1-(Benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-a). Product was obtained as TFA salt. MS (m/z): 489.18 [M+H]⁺. ¹H NMR(400 MHz, Acetonitrile-d3) δ 10.13 (s, 1H), 8.52 (s, 1H), 7.32 (dd,J=8.4, 5.8 Hz, 1H), 7.23-7.08 (m, 1H), 7.08-6.97 (m, 1H), 6.88 (t, J=8.5Hz, 2H), 5.56 (d, J=16.7 Hz, 1H), 4.83-4.69 (m, 2H), 4.64 (d, J=5.7 Hz,2H), 4.58-4.49 (m, 2H), 4.13 (d, J=13.3 Hz, 1H).

Preparation of(6S)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C4)

The synthesis of title product was taken in the same way as (C1) exceptusing(6S)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-d) as starting material instead of(6R)-1-(Benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-a). Product was obtained as TFA salt. MS (m/z): 489.19 [M+H]⁺. ¹H NMR(400 MHz, Acetonitrile-d3) δ 10.14 (s, 1H), 8.53 (d, J=14.2 Hz, 1H),7.36 (dd, J=8.5, 5.7 Hz, 1H), 7.28-7.01 (m, 2H), 6.88 (t, J=8.6 Hz, 2H),5.51 (d, J=16.3 Hz, 1H), 4.79 (q, J=14.5 Hz, 2H), 4.71-4.60 (m, 2H),4.56 (dd, J=15.0, 10.3 Hz, 2H), 4.20 (d, J=13.6 Hz, 1H).

Example 5: Preparation of(10S)-6-hydroxy-10-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide(C5)

Step 1: Synthesis of methyl1-(allyl(tert-butoxycarbonyl)amino)-3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(5)

To a suspension of methyl3-benzyloxy-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyran-2-carboxylate(2.0 g, 4.47 mmol) in a mixture of MeOH (48.0 mL) and water (8.0 mL) wasadded tert-butyl N-allyl-N-amino-carbamate (0.77 g, 4.47 mmol) andsodium bicarbonate (3.76 g, 44.7 mmol). The resulting mixture wasstirred overnight at room temperature. Water (15.0 mL) was added to thereaction and the mixture was stirred for 10 minutes. The suspension wasfiltered, filter cake was then partitioned between ethyl acetate andwater. Aqueous layer was extracted with EtOAc (×2), combined organiclayers was washed with brine, dried over sodium sulfate, filtered andconcentrated to give the desired product which was directly in nextstep. LCMS-ESI+ (m/z): calcd H+ for C₃₀H₃₀F₃N₃O₇, Theoretical: 601.20,Found: 601.99.

Step 2: Synthesis of tert-butylN-allyl-N-[3-benzyloxy-2-[[(1S)-1-methylallyl]carbamoyl]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]-1-pyridyl]carbamate(443-int-2) and1-(allylamino)-3-benzyloxy-N2-[(1S)-1-methylallyl]-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide(6)

Methyl1-(allyl(tert-butoxycarbonyl)amino)-3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(5, 2.3 g, 3.82 mmol) was dissolved in a mixture of MeOH (24.0 mL), THE(12.0 mL) and water (12.0 mL). To this mixture was added Lithiumhydroxide monohydrate (1.28 g, 30.6 mmol). The resulting mixture washeated to 60° C. with stirring for 3 hrs. The reaction was cooled toroom temperature and concentrated. The residue was diluted with EtOAc,acidified to pH ˜4 with 1 N aq HCl, organic layer was washed with brine,dried over sodium sulfate, filtered and concentrated.

The residue was then dissolved in DCM (17.0 mL) at room temperature andtreated with EDCI.HCl (975 mg, 5.11 mmol) followed by HOAt (695 mg, 5.11mmol) and DIEA (1.76 g, 13.6 mmol). (2S)-but-3-en-2-amineHCl (315 mg,4.43 mmol) was added afterwards. The newly formed mixture was stirred atroom temperature for overnight. The reaction was then diluted with DCM,washed with sat. NH₄Cl, brine, dried over sodium sulfate, filtered andconcentrated, the residue was mixed with silica gel, concentrated todryness, purified by combiflash (24 g silica gel, 0-100% EtOAc/Hexanes).Desired fractions were combined and concentrated to give tert-butylN-allyl-N-[3-benzyloxy-2-[[(1S)-1-methylallyl]carbamoyl]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]-1-pyridyl]carbamate(6) (LCMS-ESI+ (m/z): calcd H+ for C₃₃H₃₅F₃N₄O₆, Theoretical: 640.25,Found: 641.05) and1-(allylamino)-3-benzyloxy-N2-[(1S)-1-methylallyl]-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide(7) (LCMS-ESI+ (m/z): calcd H+ for C28H27F3N4O4, Theoretical: 540.20,Found: 541.02).

Compound 6 was then converted to compound 7 by treating the solution of6 (1.0 g) in DCM (10.0 mL) at room temperature with 4 N HCl in1,4-dioxane (10.0 mL, 40.0 mmol) at room temperature for 1 hour. Thereaction was concentrated, coevaporated with EtOAc×3. The residue wasthen dissolved in MeOH (20 mL), NaHCO₃ (solid) was added, stirred for 15min, filtered, and filtrate was concentrated and repurified bycombiflash to give compound 7.

Step 3: Synthesis ofI-allyl-5-hydroxy-3-[(1S)-1-methylallyl]-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-[f]1,2,4]triazine-7-carboxamide(8) and1-allyl-5-benzyloxy-3-[(1S)-1-methylallyl]-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(9)

1-(allylamino)-3-benzyloxy-N2-[(1S)-1-methylallyl]-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide(7) (350 mg, 0.647 mmol) was dissolved in a mixture of ACN (3.5 mL) andDCE (3.5 mL) at room temperature. To this mixture was addedparaformaldehyde (58.4 mg, 0.647 mmol). The resulting mixture was thenheated to 88° C. To this hot mixture was added acetic acid (0.35 mL)dropwise followed by TFA (0.15 mL) dropwise. The reaction was capped andheated for another 30 min. The reaction was cooled to rt, diluted withEtOAc, basified to pH ˜7 with sat. NaHCO₃, organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated. The residuewas purified by combiflash (12 g silica gel, 0-100% EtOAc, dry loading)to obtain the desired1-allyl-5-benzyloxy-3-[(1S)-1-methylallyl]-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(9) LCMS-ESI+ (m/z): calcd H+ for C29H27F3N4O4, Theoretical: 552.20,Found: 552.93. De-benzylated form (8) was also isolated. LCMS-ESI+(m/z):calcd H+ for C22H21F3N4O4, Theoretical: 462.15, Found: 463.02.

Compound 8 was converted back to compound 9 by treating compound 8 (120mg, 0.26 mmol) in DMF (2.6 mL) with benzyl bromide (46.6 mg, 0.272 mmol)and CESIUM CARBONATE (101 mg, 0.31 mmol) at room temperature overnight.The reaction was diluted with EtOAc, washed with water, brine, driedover sodium sulfate, filtered, mixed with silica gel, concentrated todryness, purified by combiflash (4 g silica gel, 0-100% EtOAc/Hexanes)to give 9. LCMS-ESI+ (m/z): calcd H+ for C29H27F3N4O4, Theoretical:552.20, Found: 552.92.

Step 4: Synthesis of(JOS)-6-benzyloxy-10-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide(10)

Compound 9 (130 mg, 0.23 mmol) was dissolved in DCM (29 mL), to thismixture was added Hoveyda-Grubbs II catalyst (36.9 mg, 0.059 mmol). Theresulting mixture was sparged with nitrogen for 5 minutes before it wascapped and heated at 70° C. for overnight. The reaction was then cooledto room temperature, concentrated, purified by normal phasechromatography (12 g silica gel, 0-100% EtOAc/Hexanes). LCMS-ESI+ (m/z):calcd H+ for C27H23F3N4O4, Theoretical: 524.17, Found: 524.91.

Step 5: Synthesis of(JOS)-6-hydroxy-10-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide(C5)

Compound 10 (8 mg, 0.015 mmol) was dissolved in DCM (1.0 mL) at roomtemperature and treated with TFA (1.0 mL) at room temperature for 3hours. The reaction was concentrated, redissolved in DMF, filtered andpurified by reverse phase prep HPLC. LCMS-ESI+ (m/z): calcd H+ forC20H17F3N4O4, Theoretical: 434.12, Found: 435.19. 1H NMR (400 MHz,DMSO-d6) δ 10.34 (t, J=5.8 Hz, 1H), 8.32 (s, 1H), 7.26-7.17 (m, 2H),5.75-5.66 (m, 1H), 5.46 (ddt, J=12.0, 6.2, 3.3 Hz, 1H), 5.34-5.22 (m,1H), 4.92 (d, J=14.4 Hz, 1H), 4.72 (d, J=14.4 Hz, 1H), 4.65-4.50 (m,3H), 4.27-4.17 (m, 1H), 3.70-3.62 (m, 1H), 1.29 (d, J=7.3 Hz, 3H).

Example 6: Preparation of13-benzyl-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C6)

Step 1: Synthesis of methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate

A reactor was charged with tert-butyl N-aminocarbamate (390 mg 2.95mmol), NaHCO₃ (451 mg, 5.4 mmol) in MeOH/Water (9 ml/6 ml), Then addedmethyl3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate(1200 mg, 2.68 mmol). The reaction mixture was heated to 60° C. forovernight. The reaction was cooled to room temperature, and extractedwith Ethyl Acetate (100 ml). The organic layer was concentrated undervacuum. The residue was used for next step reaction withoutpurification.MS (m/z) 562.064 [M+H]⁺.

Step 2: Synthesis of3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid

Into the above residue in MeOH (6 ml), was added 2.5 N solution of LiOH(2 ml) at rt. After 2 hours at room temperature, the reaction wasacidified by 2 N HCl and extracted with Ethyl Acetate (100 ml). Theorganic layer was concentrated under vacuum. The residue was used fornext step reaction without purification.MS (m/z) 547.96 [M+H]⁺.

Step 3: Synthesis of tert-butyl(3-(benzyloxy)-2-carbamoyl-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)carbamate

Into the solution of3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid (1720 mg, 3.14 mmol) in DMF (12 ml) was, added EDC (1205 mg, 6.28mmol), HOBt (722 mg, 4.7 mmol), DIPEA (4060 mg, 31.4 mmol) and ammoniumchloride (1680 mg. 31.4 mmol) at rt. After overnight stirring at rt, thereaction was diluted with ethyl acetate (100 ml) and wash with brine.The organic layer was dried over MgSO₄, and concentrated under vacuum.The resulting residue was purified by column chromatography. MS (m/z)547.029 [M+H]⁺. 1H NMR (400 MHz, Chloroform-d) δ 10.12 (t, J=5.7 Hz,1H), 8.58 (s, 1H), 8.50 (s, 1H), 7.37 (dq, J=4.1, 3.0, 2.4 Hz, 5H), 6.70(dd, J=8.7, 7.5 Hz, 3H), 5.84 (s, 1H), 5.33 (d, J=4.5 Hz, 3H), 4.68 (d,J=5.7 Hz, 2H), 1.45 (s, 9H).

Step 4: Synthesis ofI-amino-3-(benzyloxy)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide

Into the solution of1-amino-3-(benzyloxy)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide(200 mg, 0.366 mmol) in DCM (6 ml), was added TFA (0.5 ml) at rt. After2 hr stirring at rt, remove the solvent and excess TFA under vacuum. Theresulting residue was used for next step reaction without purification.MS (m/z) 447.075 [M+H]⁺.

Step 5: Synthesis of2-benzyl-5-(benzyloxy)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-[f]1,2,4]triazine-7-carboxamide

Into the solution of1-amino-3-(benzyloxy)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide(165 mg, 0.37 mmol) in DMF (2 ml), was added AcOH (2 ml) and2-phenylacetaldehyde (44 mg, 0.37 mmol) at rt. After heated to 100° C.for 2 h, remove DMF and excess AcOH under vacuum. The residue left overwas purified by column chromatography. MS (m/z) 549.065 [M+H]⁺.

Step 6: Synthesis of13-benzyl-8-(benzyloxy)-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

Solid KOH (106 mg, 1.9 mmol) was suspended in DMF (12 ml), the mixturesolution of2-benzyl-5-(benzyloxy)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(129 mg, 0.235 mmol) and 1,4-dibromobutane (56 mg, 0.26 mmol) in DMF (10ml) was added by syringe pump in 2 h at 0° C. The reaction mixture wasextracted with Ethyl Acetate (100 ml). The organic layer wasconcentrated under vacuum. The residue was used for next step reactionwithout purification. MS (m/z) 601.033 [M−H]⁺.

Step 7: Synthesis of13-benzyl-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C6)

Into the solution of crude13-benzyl-8-(benzyloxy)-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(129 mg, 0.225 mmol) in Toluene (5 ml), was added TFA (1 ml) at rt.After overnight stirring at rt, the solvent and excess TFA was removed.The resulting residue was purified by prep HPLC to provide titlecompound TFA salt. MS (m/z) 513.253 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 10.37 (d, J=5.9 Hz, 1H), 9.13 (s, 1H), 8.57 (s, 1H),7.28 (s, 5H), 7.11 (d, J=7.0 Hz, 1H), 6.69 (t, J=8.3 Hz, 2H), 4.90-4.60(m, 2H), 4.56-4.22 (m, 2H), 3.58-3.24 (m, 2H), 3.06-2.74 (m, 2H).

Example 7: Preparation of(1S,2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C7)

Step 1: Synthesis of methyl(R-3-benzyloxy)-1-((tert-butoxycarbonyl)(pent-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(7A)

To a reaction mixture of methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(3.5 g, 6.23 mmol), (2S)-pent-4-en-2-ol (805 mg, 9.35 mmol) andtriphenylphosphine (3.27 g, 12.5 mmol) in 7 mL of THF was addedDiisopropylazodicarboxylate (2.45 mL, 12.5 mmol). The resulting reactionmixture was stirred at room temperature for 30 min and concentrated invacuo. The residue was chromatographed on silica gel eluting withEtOAc/hexane to afford the title product. MS (m/z) 630.10 [M+H]+.

Step 2: Synthesis of(R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(pent-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid (7B)

Methyl(R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(pent-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(7A, 3.17 g, 5.04 mmol) was dissolved in MeOH (20 mL), THE (30 mL) andwater (10 mL). Lithium hydroxide monohydrate (1.05 g, 25.2 mmol) wasadded. The reaction mixture was stirred at room temperature forovernight. It was diluted with EtOAc, acidified to pH ˜4 with 1N HCl,organic layer was washed with brine, dried over sodium sulfate, filteredand concentrated to afford the title product. MS (m/z) 616.20 [M+H]+.

Step 3: Synthesis of tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)((R)-pent-4-en-2-yl)carbamate(7C)

To a reaction mixture of(R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(pent-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid (7B, 2.1 g, 3.41 mmol), (2S)-but-3-en-2-amine; hydrochloride (477mg, 4.43 mmol), EDCI.HCl (977 mg, 5.12 mmol) and HOAt (696 mg, 5.12mmol) in DCM (34 mL) was added N,N-diisopropylethylamine (2.38 mL, 13.6mmol). The reaction mixture was stirred at room temperature for 30 min,diluted with DCM, washed with sat. NH₄Cl and brine, dried over sodiumsulfate, filtered and concentrated. The residue was chromatographed onsilica gel eluting with EtOAc/hexane to afford the title product. MS(m/z) 669.83 [M+H]+.

Step 4: synthesis of tert-butyl(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-11-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecine-1-carboxylate(7D)

A solution of tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)((R)-pent-4-en-2-yl)carbamate(7C, 1.0 g, 1.5 mmol) and Grubbs catalyst 2nd generation (63.5 mg, 0.075mmol) in 500 ml of toluene was purged with Ar gas for 30 min. Theresulting solution was heated at 80° C. oil bath for 5 hours. Thereaction mixture was concentrated, and the residue was purified bycolumn chromatography on silica gel eluting EtOAc in hexane to affordthe title product. MS (m/z) 641.29 [M+H]+.

Step 5: Synthesis of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7E)

Tert-butyl(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-11-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecine-1-carboxylate(7D, 170 mg, 0.265 mmol) was dissolved in DCM (5 ml), and treated with4N HCl in 1,4-dioxane (3 ml) at room temperature for 3 hours. Then addedmore 4N HCl in 1,4-dioxane (2 mL) stirred at room temperature for 2hours. After concentrated to dryness, the residue was dissolved in EtOAcand washed with saturated NaHCO₃ and brine. the organic layer was driedover MgSO₄, filtered and concentrated to dryness followed by high vacuumdried to afford the title product. MS (m/z) 541.24 [M+H]+.

Step 6: Synthesis of(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F)

In a 8 mL sample vial,(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7E, 50 mg, 0.093) and paraformaldehyde (6.1 mg, 2.2 eq based on MW: 30)mixed with Acetonitrile (1.25 mL) and DCE (1.25 mL) at room temperature,caped and placed right away on pre-heated hot plate at 88° C. To it wasadd AcOH (0.25 mL, 10% in Acetonitrile) dropwise followed by TFA (0.25mL, 10% in DCE) dropwise. The resulting reaction mixture was thencontinued to be heated for 30 min. Cooled to room temperature and pouredonto well-stirred two-phase mixture of EtOAc-NaHCO₃ (aq). Organic phasewas separated. Aqueous layer was extracted once with EtOAc. CombinedOrganic phase was washed with brine, dried over Na₂SO₄ and filtered.Residue was concentrated to dryness and purified by RP-HPLC to affordthe title product. MS (m/z) 553.17 [M+H]+.

Step 7: Synthesis(1S,2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C7)

(1S,2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F, 30 mg, 0.054 mmol) dissolved in 2 mL of Toluene, to it was added 2mL of TFA. The mixture was stirred at room temperature for 40 minutes.Removed the solvent and purified by RP-HPLC to afford the title product.The structure was confirmed by X-Ray Crystallography. MS (m/z): 463.20[M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.42 (s, 1H), 8.42 (s, 1H),6.94-6.81 (m, 2H), 5.75-5.60 (m, 2H), 5.20 (q, J=7.1, 6.7 Hz, 1H),4.82-4.56 (m, 4H), 3.59 (p, J=6.9 Hz, 1H), 2.39 (dd, J=15.5, 7.3 Hz,1H), 2.06 (ddd, J=16.7, 7.9, 5.5 Hz, 1H), 1.29 (t, J=7.3 Hz, 6H).

Example 8: Preparation of(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C8)

(1S,2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F, 35 mg, 0.063 mmol) was dissolved in 3 mL of ethanol and 3 mL ofEtOAc and was sparged under an argon atmosphere. Palladium on carbon (10wt %, wet) (13.5 mg) was added and the mixture was sparged under ahydrogen atmosphere (1 atm, balloon). The mixture was stirred vigorouslyfor two hours and then sparged under an argon atmosphere. It wasfiltered through a pad of Celite®. The Celite® was washed with absoluteethanol and the filtrate was concentrated to dryness and the residue waspurified by RP-HPLC to afford the title product. MS (m/z): 465.200[M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.37 (s, 1H), 8.32 (s, 1H),6.94-6.81 (m, 2H), 4.87 (d, J=14.3 Hz, 1H), 4.71-4.59 (m, 3H), 4.39 (tt,J=11.5, 6.6 Hz, 1H), 2.95 (dq, J=8.6, 6.3 Hz, 1H), 2.10-1.97 (m, 2H),1.87-1.72 (m, 2H), 1.63-1.49 (m, 1H), 1.30 (q, J=12.0 Hz, 1H), 1.13 (dd,J=14.3, 6.5 Hz, 6H).

Example 9: Preparation of(1′S,5′S)-8′-hydroxy-5,5,5′-trimethyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(C9)

(1′S,5′S)-8′-hydroxy-5,5,5′-trimethyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamidewas prepared using a similar method as Example 84, except that5,5-dimethyltetrahydrofuran-3-carbaldehyde was used instead oftetrahydrofuran-3-carbaldehyde in Step 1 and only one product wasisolated from the ring closing metathesis reaction in Step 9. MS (m/z)519.24 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.79 (s, 1H), 6.91 (t,J=8.4 Hz, 2H), 6.01 (dd, J=11.9, 2.3 Hz, 1H), 5.49 (dd, J=12.0, 2.8 Hz,1H), 5.19 (d, J=14.7 Hz, 1H), 5.01 (d, J=14.7 Hz, 1H), 4.67 (s, 2H),4.37 (dt, J=7.5, 2.6 Hz, 1H), 3.73-3.61 (m, 2H), 2.52 (dd, J=13.5, 1.6Hz, 1H), 2.07-1.94 (m, 1H), 1.87 (d, J=7.4 Hz, 3H), 1.56 (s, 3H), 1.34(s, 3H).

Example 10 and 11: Preparation of(1R,2R,Z)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C10) and(1S,2R,Z)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-terahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C11)

(2R,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(9A) was prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F in example 7) using methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylateinstead of methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylatein step 1 and using allylamine; hydrochloride instead of(2S)-but-3-en-2-amine; hydrochloride in step 3. MS (m/z): 521.20 [M+H]+.

It was separated into its individual diastereomers (10B and 11A) bypreparative SFC chromatography on an IA column using ethanol asco-solvent. The separated diastereomers were dissolved in 1 mL ofToluene and 1 mL of TFA and stirred at room temperature for 1 h. afterconcentration, purified by RP-HPLC eluting with ACN/water (0.1% TFA) toprovide the title compounds C10 and C11.

Peak 1:(1R,2R,Z)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C10): MS (m/z): 431.20 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ10.37 (s, 1H), 8.35 (s, 1H), 7.44 (d, J=7.4 Hz, 1H), 6.96 (d, J=9.8 Hz,2H), 5.83 (q, J=9.7, 8.6 Hz, 1H), 5.66-5.58 (m, 1H), 5.15 (d, J=13.8 Hz,1H), 4.94 (d, J=17.8 Hz, 1H), 4.68-4.57 (m, 3H), 3.55-3.38 (m, 2H), 2.25(dt, J=16.7, 8.5 Hz, 1H), 1.97-1.86 (m, 1H), 1.15 (d, J=6.9 Hz, 3H).

Peak 2:(1S,2R,Z)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C1): MS (m/z): 431.20 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.41(s, 1H), 8.44 (s, 1H), 7.44 (q, J=8.8, 8.3 Hz, 1H), 6.97 (tt, J=10.8,3.1 Hz, 2H), 5.79-5.64 (m, 2H), 4.98-4.88 (m, 2H), 4.69-4.58 (m, 3H),3.61 (t, J=6.7 Hz, 1H), 3.53 (dd, J=18.0, 4.0 Hz, 1H), 2.42 (dd, J=15.4,7.1 Hz, 1H), 2.16-2.03 (m, 1H), 1.29 (d, J=7.1 Hz, 3H).

Example 12: Preparation of(1R,2S,6R,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C12)

Compound 12 was prepared in a manner similar to(1S,2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C7 in example 7) using (2R)-pent-4-en-2-ol instead of(2S)-pent-4-en-2-ol in step 1 and using (2R)-but-3-en-2-amine;hydrochloride instead of (2S)-but-3-en-2-amine; hydrochloride in step 3.MS (m/z): 431.20 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.43 (s,1H), 8.42 (s, 1H), 6.94-6.81 (m, 2H), 5.75-5.60 (m, 2H), 5.20 (q, J=7.5Hz, 1H), 4.84-4.53 (m, 4H), 3.58 (q, J=6.9 Hz, 1H), 2.39 (dd, J=15.2,7.2 Hz, 1H), 2.12-2.00 (m, 1H), 1.29 (t, J=7.3 Hz, 6H).

Example 13: Preparation of(1S,2R)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C13)

Compound 13 was prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C8) in example 8 using(1S,2R,Z)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(11) instead of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F). MS (m/z): 433.20 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 10.39(s, 1H), 8.34 (s, 1H), 7.57-7.20 (m, 1H), 7.03-6.91 (m, 2H), 4.86 (d,J=14.3 Hz, 1H), 4.78 (d, J=14.6 Hz, 1H), 4.60 (d, J=5.6 Hz, 2H), 4.14(dd, J=13.4, 5.9 Hz, 1H), 3.39-2.97 (m, 2H), 1.97-1.87 (m, 2H), 1.75 (d,J=6.5 Hz, 1H), 1.63 (dt, J=16.9, 9.1 Hz, 1H), 1.55-1.20 (m, 2H), 1.17(d, J=6.5 Hz, 3H).

Example 14: Preparation of(1R,2S,6R)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C14)

Compound 14 was prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C8) in example 8 using(1R,2S,6R,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamideinstead of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F). MS (m/z): 465.20 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.37(s, 1H), 8.32 (s, 1H), 6.94-6.81 (m, 2H), 4.87 (d, J=14.3 Hz, 1H),4.74-4.58 (m, 3H), 4.39 (ddd, J=11.8, 6.7, 4.8 Hz, 1H), 3.01-2.89 (m,1H), 2.07-1.97 (m, 1H), 1.87-1.72 (m, 2H), 1.56 (dt, J=16.6, 10.1 Hz,1H), 1.30 (q, J=12.0 Hz, 1H), 1.13 (dd, J=14.5, 6.5 Hz, 6H).

Example 15: Preparation of(1R,2R)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C15)

Compound 15 was prepared in a manner similar to(1R,2R,Z)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C8) in example 8 using(1R,2R,Z)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(10) instead of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F). MS (m/z): 433.20 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ 11.50(s, 1H), 10.41 (s, 1H), 8.32 (d, J=16.7 Hz, 1H), 7.49-7.38 (m, 1H), 6.97(ddt, J=13.4, 8.5, 3.0 Hz, 2H), 5.13 (d, J=14.1 Hz, 1H), 4.80 (t, J=14.9Hz, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.22 (dt, J=13.8, 4.6 Hz, 1H), 3.57 (p,J=7.2 Hz, 1H), 3.02 (ddd, J=14.0, 10.1, 4.2 Hz, 1H), 1.96 (d, J=2.5 Hz,3H), 1.70-1.55 (m, 1H), 1.53-1.16 (m, 2H), 1.13 (d, J=7.0 Hz, 3H).

Example 16: Preparation of(1S,2R,Z)-9-hydroxy-2-methyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C16)

(2R,Z)-9-(benzyloxy)-2-methyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(16A) was prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F in example 7) using allylamine; hydrochloride instead of(2S)-but-3-en-2-amine; hydrochloride in step 3. MS (m/z): 539.20 [M+H]+.

It was separated into its individual diastereomers (peak 1 and peak 2)by RP-HPLC eluting with acetonitrile and water (with 0.1% TFA). Takepeak 2 (23 mg, 0.043 mmol) dissolved in 0.5 mL of Toluene and 0.5 mL ofTFA and stirred at room temperature for 1 hour. After concentration,purified by RP-HPLC eluting with ACN/water (0.1% TFA) to provide thetitle compound. MS (m/z): 449.10 [M+H]+. ¹H NMR (400 MHz,Acetonitrile-d₃) δ 10.41 (s, 1H), 8.42 (s, 1H), 6.87 (t, J=8.7 Hz, 2H),5.72 (q, J=11.7, 9.1 Hz, 2H), 4.92 (d, J=15.7 Hz, 2H), 4.64 (d, J=14.6Hz, 3H), 3.82-3.11 (m, 2H), 2.46-2.35 (m, 1H), 2.08 (dt, J=13.7, 6.3 Hz,1H), 1.28 (d, J=7.2 Hz, 3H).

Example 17: Preparation of(1S,2R)-9-hydroxy-2-methyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C17)

Compound 17 was prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C8) in example 8 using(1S,2R,Z)-9-hydroxy-2-methyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(16) instead of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F). MS (m/z): 451.20 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.38(s, 1H), 8.33 (s, 1H), 6.94-6.81 (m, 2H), 4.85 (d, J=14.4 Hz, 1H), 4.76(d, J=14.5 Hz, 1H), 4.62 (d, J=5.6 Hz, 2H), 4.14 (dt, J=14.0, 7.0 Hz,1H), 3.06 (dt, J=13.8, 4.4 Hz, 2H), 1.93 (d, J=14.4 Hz, 3H), 1.75 (t,J=8.3 Hz, 1H), 1.63 (dt, J=16.9, 8.9 Hz, 1H), 1.44 (q, J=10.1 Hz, 1H),1.16 (d, J=6.5 Hz, 3H).

Example 18: Preparation of(1S,2R,6R,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C18)

(2R,6R,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(18A) was prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F in example 7) using (2R)-but-3-en-2-amine; hydrochloride instead of(2S)-but-3-en-2-amine; hydrochloride in step 3. MS (m/z): 553.30 [M+H]+.

It was separated into its individual diastereomers top spot and lowerspot) by silica gel chromatography eluting with EtOAc/hexane. Took lowerspot (15 mg, 0.027 mmol), dissolved in 0.5 mL of Toluene and 0.5 mL ofTFA and stirred at room temperature for 1 hour. After concentration,purified by RP-HPLC eluting with ACN/water (0.1% TFA) to provide thetitle compound (18). MS (m/z): 463.20 [M+H]+. ¹H NMR (400 MHz,Acetonitrile-d₃) δ 10.38 (s, 1H), 8.34 (s, 1H), 6.94-6.81 (m, 2H),5.85-5.72 (m, 1H), 5.53 (dt, J=11.6, 1.6 Hz, 1H), 5.27 (d, J=7.9 Hz,1H), 4.96 (d, J=13.7 Hz, 1H), 4.73 (d, J=13.7 Hz, 1H), 4.62 (d, J=5.7Hz, 2H), 3.48-3.35 (m, 1H), 2.29-2.15 (m, 1H), 1.96-1.87 (m, 1H), 1.27(d, J=7.4 Hz, 3H), 1.12 (d, J=7.0 Hz, 3H).

Example 19 and 20: Preparation of(1R,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C19) and(1S,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C20)

(2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(19A) was prepared in a manner similar to(1S,2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7 in example 7) using (2R)-pent-4-en-2-ol instead of(2S)-pent-4-en-2-ol in step 1. MS (m/z): 463.20 [M+H]+.

It was separated into its individual diastereomers (peak 1 and peak 2)by preparative SFC chromatography on an AZ-H column using methanol asco-solvent.

Peak 1:(1R,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(19): MS (m/z): 463.20 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ 11.45(s, 1H), 10.38 (s, 1H), 8.33 (s, 1H), 6.94-6.81 (m, 2H), 5.85-5.72 (m,1H), 5.53 (dt, J=11.5, 1.6 Hz, 1H), 5.27 (d, J=8.0 Hz, 1H), 4.96 (d,J=13.7 Hz, 1H), 4.72 (d, J=13.6 Hz, 1H), 4.62 (d, J=5.7 Hz, 2H),3.48-3.35 (m, 1H), 2.29-2.15 (m, 1H), 1.97-1.85 (m, 1H), 1.27 (d, J=7.4Hz, 3H), 1.12 (d, J=7.0 Hz, 3H).

Peak 2:(1S,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(20): MS (m/z): 463.20 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.44(s, 1H), 8.39 (s, 1H), 6.87 (t, J=8.5 Hz, 2H), 5.69 (d, J=12.1 Hz, 1H),5.59 (dd, J=18.9, 9.5 Hz, 1H), 4.93 (d, J=14.2 Hz, 1H), 4.76-4.42 (m,3H), 4.06 (s, 1H), 3.55 (s, 1H), 2.60 (s, 1H), 2.07 (t, J=7.4 Hz, 1H),1.81 (d, J=7.4 Hz, 3H), 1.29 (d, J=7.1 Hz, 3H).

Example 21: Preparation of(1R,2S,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C21)

Prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C8) in example 8 using(1R,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C19) instead of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F). MS (m/z): 465.20 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.40(s, 1H), 8.29 (s, 1H), 6.91-6.83 (m, 2H), 4.84 (d, J=14.4 Hz, 1H), 4.77(d, J=14.5 Hz, 1H), 4.69-4.51 (m, 3H), 3.57 (q, J=7.1 Hz, 1H), 1.96-1.83(m, 2H), 1.80-1.54 (m, 3H), 1.39 (dd, J=13.0, 6.2 Hz, 1H), 1.18 (dd,J=7.0, 2.3 Hz, 6H).

Example 22: Preparation of(1S,2R,6R)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C22)

Prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C8) in example 8 using(1S,2R,6R,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C18) instead of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F). MS (m/z): 465.20 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 10.41(s, 1H), 8.28 (s, 1H), 6.87 (t, J=8.5 Hz, 2H), 4.84 (d, J=14.4 Hz, 1H),4.77 (d, J=14.4 Hz, 1H), 4.65-4.52 (m, 3H), 3.55 (q, J=7.0 Hz, 1H),1.95-1.84 (m, 1H), 1.79-1.54 (m, 3H), 1.44-1.34 (m, 1H), 1.18 (dd,J=6.9, 2.5 Hz, 7H).

Example 23: Preparation of(1S,2S,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C23)

Compound 23 was prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C8) in example 8 using(1S,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C20): instead of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F). MS (m/z): 465.20 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s,1H), 10.41 (t, J=5.8 Hz, 1H), 8.28 (s, 1H), 7.21 (t, J=8.6 Hz, 2H), 6.53(s, OH), 5.00 (d, J=14.4 Hz, 1H), 4.88 (d, J=14.6 Hz, 1H), 4.60 (dd,J=14.6, 6.0 Hz, 1H), 4.51 (dd, J=14.6, 5.7 Hz, 1H), 3.53-3.50 (m, 2H),2.11-1.96 (m, 1H), 1.76 (q, J=12.1 Hz, 1H), 1.70-1.61 (m, 2H), 1.53 (d,J=6.9 Hz, 5H), 1.32 (d, J=7.1 Hz, 3H).

Example 24. Preparation of(1S,2R,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C24) Step 1: Preparation of methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate

Methyl3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate(60.0 g, 134 mmol, 1.00 eq) was mixed with MeOH (300 mL) and H₂O (60.0mL). BocNHNH₂ (19.5 g, 147 mmol, 1.10 eq) and NaHCO₃ (22.5 g, 268 mmol,10.4 mL, 2.00 eq) were added at room temperature. Reaction mixture wasthen stirred at 55° C. for 16 hours. The reaction mixture was placedunder vacuum to remove most of the MeOH. The resulting residue wasdiluted with H₂O (200 mL) and the crude product was extracted with EtOAc(1500 mL). The organic layer was washed with brine (500 mL), dried withNa₂SO₄ and was concentrated in vacuum. The resulting slurry was purifiedwith silica gel chromatography with Petroleum ether: Ethyl acetate=5:1to afford product. MS (m/z): 562.5 [M+H].

Step 2: Preparation of methyl3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate

Methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(5 g, 8.9 mmol) was dissolved in THF (100 mL) at rt. The solution wascooled down to 0° C. under argon. But-3-en-2-ol (963 mg, 13.4 mmol) andPh₃P (3.5 g, 13.4 mmol) were added sequentially. Then DIAD (2.7 g, 13.4mmol) was added drop-wise over 5 min. The resulting reaction was stirredat 0° C. for 5 min. The cold bath was removed. The reaction mixture wasstirred at rt for 17 hr. The reaction mixture was concentrated todryness. Residue was purified on silica gel column with 0-100% EtOAc/Hexto obtain the product. MS (m/z): 616.0 [M+H].

Step 3: Preparation of3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid

Methyl3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(5.4 g, 8.9 mmol) was mixed with MeOH (125 mL) and water (100 mL) at rt.LiOH (5M in water) (11 ml) was added. Fitted with air condenser,reaction mixture was heated to 73° C. with stirring for 3.5 hr. Addedmore LiOH (5M) (2 mL). Reaction mixture was then stirred at 40° C. for17 hr. Reaction mixture was concentrated carefully for removal of MeOH.The residue was diluted and rinsed with some water and was acidifiedwith 1N HCl to pH=3. EtOAc (200 mL) was added for extraction. Organicphase was separated. Aqueous layer was extracted with more EtOAc (100mL). The combined organic phases were washed with water and brine,separated, dried over Na₂SO₄, filtered, and concentrated to afford theproduct. MS (m/z): 602.0 [M+H].

Step 4: Preparation of tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)(but-3-en-2-yl)carbamate(S)-but-3-en-2-amine hydrochloride

3-(Benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid (4.75 g, 7.9 mmol) was dissolved in DMF (20 mL) at rt. DIEA (6.1 g,47.4 mmol) was added. Then (S)-but-3-en-2-amine hydrochloride (1.27 g,11.8 mmol) and HATU (4.5 g, 11.8 mmol) were added sequentially. Theresulting reaction mixture was stirred at rt for 17 hrs. The reactionmixture was diluted with EtOAc (100 mL) and was then treated with NaHCO₃(saturated aqueous solution, 100 mL) and water (100 mL). Organic phasewas separated and washed with water (50 mL) and brine (50 mL). The finalorganic phase was concentrated to remove solvents. The residue waspurified on silica gel column with 0-100% EtOAc/Hex to afford product.MS (m/z): 655.0 [M+H].

Step 5: Preparation of3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-1-(but-3-en-2-ylamino)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide

Tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)(but-3-en-2-yl)carbamate(4.42 g, 6.75 mmol) was dissolved in DCM (10 mL) at rt. HCl (4M indioxane) (10 mL) was added. Reaction mixture was stirred at rt for 6hrs. Reaction mixture was then concentrated to dryness. The residue waspartitioned between EtOAc (100 mL) and NaHCO₃ (saturated aqueoussolution, 100 mL). Organic phase was separated, washed with brine andwas dried over Na₂SO₄. The solvent was removed to afford the product. MS(m/z): 555.3 [M+H].

Step 6: Preparation of5-(benzyloxy)-3-((S)-but-3-en-2-yl)-1-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

3-(Benzyloxy)-N2-((S)-but-3-en-2-yl)-1-(but-3-en-2-ylamino)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide(1.845 g, 3.33 mmol) was dissolved in acetonitrile (18.45 mL) anddichloroethane (18.45 mL) at rt. Paraformaldehyde (200 mg, 6.66 mmol)was added. The resulting mixture was placed onto pre-heated hot bath at88° C. Then AcOH (0.9 mL) and TFA (0.9 mL) were added sequentially intothe pre-heated reaction mixture within 5 min. The resulting reactionmixture was then sealed and heated with stirring for 30 min. Theresulting reaction mixture was then concentrated to dryness to removeall solvents and acids. The resulting crude material was then dissolvedin DMF (17 mL). K₂CO₃ (2.76 g, 20 mmol) and benzyl bromide (2.56 g, 15mmol) were added sequentially. The reaction mixture was then heated at100° C. for 3 hrs. Reaction mixture was then diluted with EtOAc (100 mL)and was then treated with NaHCO₃ (saturated aqueous solution) (100 mL)and water (100 mL). The organic phase was separated and washed withwater (50 mL) and brine (50 mL). The solvent was removed in vacuum. Theresidual crude product was purified on silica gel column with 0-100%EtOAc/Hex to afford the product. MS (m/z): 567.2 [M+H].

Step 7: Preparation of(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(A),(1S,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(B) and(1R,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C)

5-(Benzyloxy)-3-((S)-but-3-en-2-yl)-1-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(931 mg, 1.64 mmol) was dissolved in dichloroethane (88 mL) at rt. Argonwas bubbled through the reaction solution for 5 min. HG-M720 catalyst(103.4 mg, 0.164 mmol) was then added with stirring. The purging withargon was continued for 10 min. The reaction mixture was then heatedwith stirring under argon atmosphere for 48 hrs. The resulting reactionmixture was then concentrated to dryness. The crude material waspurified on silica gel column with 0-100% EtOAc/Hex to afford threediastereomers there can be separated:(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(A), 334 mg. MS (m/z): 539.2 [M+H] and(1S,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(B), 96 mg. MS (m/z): 539.2 [M+H] and(1R,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C), 16 mg, MS (m/z): 539.2 [M+H]. The absolute configurations of thosetwo compounds are yet to be determined.

Preparation of(1S,2R,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C24)

(1S,2R,5S)-8-(Benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(110 mg, 0.188 mmol) was dissolved in toluene (1 mL) at rt. TFA (1 mL)was added carefully with stirring. The resulting reaction mixture wasstirred at rt for 17 hrs. Reaction mixture was then concentrated todryness. The residue was taken up in MeOH and was purified with reversephase prep-HPLC with 0-100% CH₃CN in water with 0.1% TFA to afford thedesired product. Lyophilization afford product as mono TFA salt. 50 mg.MS (m/z): 449.2 [M+H]. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.21 (t,J=5.9 Hz, 1H), 8.38 (s, 1H), 6.87 (t, J=8.5 Hz, 2H), 5.65 (dt, J=11.4,2.4 Hz, 1H), 5.47-5.27 (m, 2H), 5.01 (d, J=14.4 Hz, 1H), 4.62 (d, J=5.8Hz, 2H), 4.57 (d, J=14.3 Hz, 1H), 3.82 (tp, J=6.6, 3.3 Hz, 1H), 1.35 (d,J=2.0 Hz, 3H), 1.33 (d, J=2.6 Hz, 3H).

Example 25: Preparation of(1S,2S,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C25)

(1S,2S,5S)-8-(Benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(78 mg, 0.145 mmol) was dissolved in toluene (1 mL) at rt. TFA (1 mL)was added carefully with stirring. The resulting reaction mixture wasstirred at rt for 17 hrs. Reaction mixture was then concentrated todryness. The residue was taken up in MeOH and was purified with reversephase prep-HPLC with 0-100% CH₃CN in water with 0.1% TFA to afford thedesired product. Lyophilization afford product as mono TFA salt. 34 mg.MS (m/z): 449.2 [M+H]. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.28 (s,1H), 8.44 (s, 1H), 7.11-6.61 (m, 2H), 5.61 (ddd, J=12.3, 3.3, 2.1 Hz,1H), 5.50-5.27 (m, 2H), 4.93 (d, J=14.4 Hz, 1H), 4.72 (d, J=14.4 Hz,1H), 4.66-4.53 (m, 3H), 1.35 (d, J=7.2 Hz, 3H), 1.01 (d, J=7.4 Hz, 3H).

Example 26: Preparation of(1R,2S,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C26)

(1R,2S,5S)-8-(Benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(16 mg, mmol) was dissolved in toluene (1 mL) at rt. TFA (1 mL) wasadded carefully with stirring. The resulting reaction mixture wasstirred at rt for 17 hrs. Reaction mixture was then concentrated todryness. The residue was purified with 0-100% EtOAc in Hexane to affordproduct as neural form. 8 mg. MS (m/z): 449.2 [M+H]. 1H NMR (400 MHz,Acetonitrile-d3) δ 10.30 (s, 1H), 8.40 (s, 1H), 6.97-6.77 (m, 2H), 5.80(ddd, J=11.7, 2.7, 1.9 Hz, 1H), 5.45 (ddd, J=11.7, 4.2, 2.4 Hz, 1H),4.81-4.69 (m, 2H), 4.65-4.59 (m, 2H), 4.32 (dtt, J=7.5, 5.0, 2.5 Hz,1H), 4.01 (ddq, J=7.0, 4.8, 2.4 Hz, 1H), 1.79 (d, J=7.5 Hz, 3H), 1.40(d, J=7.0 Hz, 3H).

Example 27: Preparation of(1S,2R,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C27)

(1S,2R,5S)-8-(Benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(92.8 mg, 0.172 mmol) was dissolved in MeOH (10 mL). Pd—C (10%) (23 mg)was added. Hydrogenolysis was taken with H₂ balloon at rt for 7 hrs.Reaction mixture was filtered through celite. Filtrate was collected andconcentrated to dryness. The residue was taken up in MeOH and waspurified with reverse phase prep-HPLC with 0-100% CH₃CN in water with0.1% TFA to afford the desired product. Lyophilization afford product asmono TFA salt. 34 mg. MS (m/z): 451.3 [M+H]. 1H NMR (400 MHz,Acetonitrile-d3) δ 10.37 (s, 1H), 8.43 (s, 1H), 7.02-6.78 (m, 2H),4.71-4.45 (m, 5H), 3.51 (dq, J=7.2, 3.6 Hz, 1H), 2.02 (ddd, J=8.2, 6.1,3.3 Hz, 1H), 1.78-1.66 (m, 1H), 1.55 (dt, J=8.6, 3.3 Hz, 2H), 1.31 (d,J=7.2 Hz, 3H), 1.27 (d, J=6.8 Hz, 3H).

Example 28: Preparation of(1S,2S,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C28)

(1S,2S,5S)-8-(Benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(18 mg, 0.172 mmol) was dissolved in MeOH (8 mL). Pd—C (10%) (10 mg) wasadded. Hydrogenolysis was taken with H₂ balloon at rt for 7 hrs.Reaction mixture was filtered through celite. Filtrate was collected andconcentrated to dryness. The residue was taken up in MeOH and waspurified with reverse phase prep-HPLC with 0-100% CH₃CN in water with0.1% TFA to afford the desired product. Lyophilization afford product asmono TFA salt. 7 mg. MS (m/z): 451.3 [M+H]. 1H NMR (400 MHz,Acetonitrile-d3) δ 10.36 (s, 1H), 8.34 (s, 1H), 6.98-6.77 (m, 2H),4.76-4.59 (m, 5H), 3.41 (dd, J=11.6, 6.3 Hz, 1H), 2.20 (dt, J=14.2, 6.8Hz, 1H), 1.80-1.49 (m, 2H), 1.26 (d, J=6.7 Hz, 3H), 1.30-1.17 (m, 1H),1.08 (d, J=6.9 Hz, 3H).

Example 29: Preparation of(1S,2R,5S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C29) Step 1: Preparation of methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate

Methyl3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate(15 g, 34.9 mmol) was mixed with MeOH (100 mL) and H₂O (30.0 mL).BocNHNH₂ (5 g, 37.8 mmol) and NaHCO₃ (5.87 g, 69.9 mmol) were added atroom temperature. Reaction mixture was then stirred at 55° C. for 16hours. The reaction mixture was placed under vacuum to remove the mostMeOH. The resulting residue was diluted with H₂O (200 mL) and the crudeproduct was extracted with EtOAc (500 mL). The organic layer was washedwith brine (500 mL), dried with Na₂SO₄ and was concentrated in vacuum.The resulting slurry was purified with silica gel chromatography withHexane:Ethyl acetate=5:1 to afford product 18 g as white solid. MS(m/z): 543.95 [M+H].

Step 2: Preparation of methyl3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate

Methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(10.5 g, 19.3 mmol) was dissolved in THE (200 mL) at rt. The solutionwas cooled down to 0° C. under argon. But-3-en-2-ol (2.37 g, 32.8 mmol)and Ph₃P (8.6 g, 32.8 mmol) were added sequentially. Then DIAD (6.64 g,32.8 mmol) was added drop-wise over 5 min. The resulting reactionmixture was slightly orange solution. Let it be stirred at 0° C. for 5min. The cold bath was removed. Let reaction mixture be stirred at rtfor 17 hr. The reaction mixture was concentrated to dryness. Residue waspurified on silica gel column with 0-100% EtOAc/Hex to obtained product10 g. MS (m/z): 598.04 [M+H].

Step 3: Preparation of3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid

Methyl3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(12.5 g, 20.9 mmol) was mixed with MeOH (200 mL) and water (100 mL) atrt. LiOH (5M in water) (33.5 mL, 167 mmol) was added. Fitted with aircondenser, reaction mixture was heated to 63° C. with stirring for 17hr. Reaction mixture was concentrated carefully for removal of MeOH. Theresidue was diluted and rinsed with some water and was acidified with 1NHCl to pH=3. Solid appeared. EtOAc (200 mL) was added for extraction.Organic phase was separated. Aqueous layer was extracted with more EtOAc(100 mL). The combined organic phases were washed with water and brine.It was dried over Na₂SO₄, filtered and concentrated to afford the acidproduct 9 g. MS (m/z): 584.30 [M+H].

Step 4: Preparation of tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)pyridin-1(4H)-yl)(but-3-en-2-yl)carbamate

3-(Benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid (5 g, 8.56 mmol) was dissolved in DMF (40 mL) at rt. DIEA (5.52 g,42.8 mmol) and the reaction mixture was cooled down with ice-water bath.HATU (6.52 g, 17.14 mmol) was added in one portion. Then the reactionmixture was warmed up to rt with stirring for 1 h. Then(S)-but-3-en-2-amine hydrochloride (2.3 g, 21.4 mmol) was added. Theresulting reaction mixture was stirred at rt for 17 hrs. The reactionmixture was diluted with EtOAc (200 mL) and was then treated with NaHCO₃(saturated aqueous solution, 100 mL) and water (100 mL). Organic phasewas separated and washed with water (50 mL) and brine (50 mL). The finalorganic phase was concentrated to remove solvents. The residue was pureenough for next step. 4 g. MS (m/z): 637.03 [M+H].

Step 5: Preparation of3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-1-(but-3-en-2-ylamino)-4-oxo-N5-(2,4-difluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide

Tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)pyridin-1(4H)-yl)(but-3-en-2-yl)carbamate(4 g, 6.29 mmol) was dissolved in DCM (10 mL) at rt. HCl (4M in dioxane)(10 mL) was added. Reaction mixture was stirred at rt for 6 hrs.Reaction mixture was then concentrated to dryness. The residue waspartitioned between EtOAc (100 mL) and NaHCO₃ (saturated aqueoussolution, 100 mL). Organic phase was separated, washed with brine andwas dried over Na₂SO₄. The solvent was removed to afford the product 3g. MS (m/z): 537.17 [M+H].

Step 6: Preparation of5-(benzyloxy)-3-((S)-but-3-en-2-yl)-1-(but-3-en-2-yl)-4,6-dioxo-N-(2,4-difluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

3-(Benzyloxy)-N2-((S)-but-3-en-2-yl)-1-(but-3-en-2-ylamino)-4-oxo-N5-(2,4-difluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide(2.52 g, 4.7 mmol) was dissolved in acetonitrile (25 mL) anddichloroethane (25 mL) at rt. Paraformaldehyde (278 mg, 9.25 mmol) wasadded. The resulting slurry was placed onto pre-heated hot bath at 88°C. Then AcOH (1.15 mL) and TFA (1.15 mL) were added sequentially intothe pre-heated reaction mixture within 5 min. The resulting reactionmixture was then sealed and heated with stirring for 30 min. Theresulting reaction mixture was then concentrated to dryness to removeall solvents and acids. The resulting crude material was then dissolvedin DMF (17 mL). K₂CO₃ (10 g, 72.4 mmol) and benzyl bromide (6.63 g, 38.8mmol) were added sequentially. The reaction mixture was then heated at100° C. for 3 hrs. Reaction mixture was then diluted with EtOAc (100 mL)and was then treated with NaHCO₃ (saturated aqueous solution) (100 mL)and water (100 mL). The organic phase was separated and washed withwater (50 mL) and brine (50 mL). The solvent was removed in vacuum. Theresidual crude product was purified on silica gel column with 0-100%EtOAc/Hex to afford product 1 g. MS (m/z): 549.2 [M+H].

Step 7: Preparation of(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamideand(1S,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

5-(Benzyloxy)-3-((S)-but-3-en-2-yl)-1-(but-3-en-2-yl)-4,6-dioxo-N-(2,4-difluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(753 mg, 1.37 mmol) was dissolved in dichloroethane (83 mL) at rt. Argonwas bubbled through the reaction solution for 5 min. HG-M720 catalyst(146.4 mg, 0.233 mmol) was then added with stirring. The purging withargon was continued for 10 min. The reaction mixture was then heatedwith stirring under argon atmosphere for 48 hrs. The resulting reactionmixture was then concentrated to dryness. The crude material waspurified on silica gel column with 0-100% EtOAc/Hex to afford twoproducts as single diastereomers:(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide,230 mg. MS (m/z): 521.2 [M+H] and(1S,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide,15 mg. MS (m/z): 521.2 [M+H]. The absolute configurations of those twocompounds are yet to be determined.

Step 8: Preparation of(1S,2R,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,5S)-8-(Benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(230 mg, 0.188 mmol) was dissolved in toluene (1 mL) at rt. TFA (1 mL)was added carefully with stirring. The resulting reaction mixture wasstirred at rt for 17 hrs. Reaction mixture was then concentrated todryness. The residue was taken up in MeOH and was purified with reversephase prep-HPLC with 0-100% CH₃CN in water with 0.1% TFA to afford thedesired product. Lyophilization afford product as mono TFA salt. 150 mg.MS (m/z): 431.2 [M+H]. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.21 (s,1H), 8.39 (s, 1H), 7.44 (td, J=8.8, 6.5 Hz, 1H), 7.21-6.84 (m, 2H), 5.66(dt, J=11.4, 2.4 Hz, 1H), 5.46-5.32 (m, 2H), 5.02 (d, J=14.4 Hz, 1H),4.67-4.50 (m, 3H), 3.84 (qq, J=6.6, 3.0 Hz, 1H), 1.35 (dd, J=7.1, 4.1Hz, 6H).

Example 30: Preparation of(1S,2S,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C30)

(1S,2S,5S)-8-(Benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(15 mg, 0.0288 mmol) was dissolved in toluene (1 mL) at rt. TFA (1 mL)was added carefully with stirring. The resulting reaction mixture wasstirred at rt for 17 hrs. Reaction mixture was then concentrated todryness. The residue was taken up in MeOH and was purified with reversephase prep-HPLC with 0-100% CH₃CN in water with 0.1% TFA to afford thedesired product. Lyophilization afford product as mono TFA salt. 5 mg.MS (m/z): 431.2 [M+H]. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.27 (s,1H), 8.45 (s, 1H), 7.44 (td, J=8.8, 6.5 Hz, 1H), 6.97 (dddd, J=10.7,5.2, 4.3, 2.5 Hz, 2H), 5.62 (ddd, J=12.2, 3.3, 2.1 Hz, 1H), 5.46-5.31(m, 2H), 4.94 (d, J=14.4 Hz, 1H), 4.73 (d, J=14.4 Hz, 1H), 4.61 (d,J=6.1 Hz, 3H), 1.36 (d, J=7.2 Hz, 3H), 1.03 (d, J=7.4 Hz, 3H).

Example 31: Preparation of(1S,2S,5S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C31)

A solution of(1S,2S,5S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(Example 30, 0.291 mmol, 125 mg) in EtOH (9 mL) was evacuated andback-filled with argon (5× cycles) then treated with 10% Pd/C (25 mg)and further evacuated and back-filled with argon (5× cycles) followed byhydrogen (5× cycles). The reaction mixture was stirred at roomtemperature under a hydrogen balloon overnight then filtered acrossCelite, washed with EtOH and concentrated. The resulting residue wasdissolved again in EtOH (22 mL) and treated with 10% Pd/C (50 mg) andhydrogen per above. After 4 hours, the reaction mixture was filteredacross Celite, washed with EtOH and concentrated then purified bypreparative HPLC (10-100% MeCN in water with 0.1% TFA) and lyophilizedto afford the title compound as the trifluoroacetic acid salt (62 mg,39% yield). MS (m/z) 433.25 [M+H]+. ¹H NMR (400 MHz, Methanol-d4) δ 8.43(s, 1H), 7.43 (td, J=8.5, 6.4 Hz, 1H), 7.02-6.88 (m, 2H), 4.85-4.76 (m,2H), 4.69 (dt, J=10.6, 6.7 Hz, 1H), 4.63 (s, 2H), 3.55-3.44 (m, 1H),2.22 (dt, J=14.2, 6.8 Hz, 1H), 1.75 (dt, J=15.0, 11.3 Hz, 1H), 1.66 (dd,J=15.7, 6.9 Hz, 1H), 1.30 (d, J=6.7 Hz, 3H), 1.36-1.20 (m, 1H), 1.11 (d,J=6.8 Hz, 3H).

Example 32: Preparation of(1S,2R,3R,4S,5S)-8-hydroxy-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:(C32)

Preparation of(1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

In a 50-mL flask,(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(Example 24, step 7, A) (140 mg, 0.26 mmol) was dissolved in acetone (8mL) and water (1 mL) mixture, then was cooled down to 0° C. in ice-waterbath. 4-Methylmorpholine N-oxide (50% in water, 0.1 mL, 2 eq.) wasslowly added into above reaction solution. Then 2.5% osmium tetroxide(0.01 mL, 4% eq.) was added. The mixture was stirred at 0° C. and warmup to r.t. for 2 days. The reaction was quenched by adding aqueous 10%sodium sulfite solution. The reaction mixture was extracted using (1:1)EtOAc:n-BnOH. The organic layer was concentrate down, and purified viasilica column (eluting with 0-10% MeOH/DCM) to give(1S,2R,3S,4R,5S)-8-(benzyloxy)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(non-polar, minor product) and(1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(polar, major product). MS (m/z) 573.3 [M+H]⁺.

Preparation of(1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide,(1S,2R,3R,4S,5S)-8-(benzyloxy)-3-hydroxy-4-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide,and(1S,2R,3R,4S,5S)-8-(benzyloxy)-4-hydroxy-3-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

In a 50-mL flask,(1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(77 mg, 0.134 mmol) was dissolved in DMF (3 mL), then was cooled down to0° C. in ice-water bath. Sodium hydride (60%, 11 mg, 2.2 eq.) was addedinto above reaction solution. After 10 minutes, methyl iodide (dilutedwith DCM to 100 times dilute, 1 mL, 1.3 eq.) was added. The mixture wasstirred at 0° C. for 30 minutes. LC-MS showed bis-Me product, and twomono-Me products, and some starting material. The reaction was quenchedby adding aqueous saturated sodium bicarbonate solution. The reactionmixture was extract using ethyl acetate. The organic layer wasconcentrated down, and purified via preparative HPLC, eluting 10-100%acetonitrile (0.1% TFA) in water (0.1% TFA) to give(1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamideMS (m/z) 601.3 [M+H]⁺) and(1S,2R,3R,4S,5S)-8-(benzyloxy)-3-hydroxy-4-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(polar, major mono-Me product MS (m/z) 587.3 [M+H]⁺) and(1S,2R,3R,4S,5S)-8-(benzyloxy)-4-hydroxy-3-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(non-polar, minor mono-Me product MS (m/z) 587.3 [M+H]⁺)

Preparation of(1S,2R,3R,4S,5S)-8-hydroxy-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C32)

(1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(15 mg) was dissolved in toluene (0.5 mL), trifluoroacetic acid (1 mL)was added. The reaction was stirred at r.t. for 2 hours. The reactionwas concentrated down and purified via preparative HPLC, eluting 10-100%acetonitrile (0.1% TFA) in water (0.1% TFA) to give to 7.2 mg the titlecompound. MS (m/z) 511.3 [M+H]⁺. 1H NMR (400 MHz, Acetonitrile-d3) δ10.40 (s, 1H), 8.45 (s, 1H), 6.99-6.80 (m, 2H), 4.70-4.59 (m, 2H), 4.52(t, J=14.8 Hz, 2H), 4.26-4.12 (m, 1H), 3.81 (d, J=7.6 Hz, 1H), 3.61 (d,J=3.1 Hz, 1H), 3.47 (d, J=8.8 Hz, 1H), 3.36 (s, 3H), 3.09 (s, 3H),1.48-1.25 (m, 6H).

Example 33: Preparation of(1S,2R,4R,5S)-8-hydroxy-4-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C33)

Preparation of(1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamideand(1S,2R,3S,5S)-8-(benzyloxy)-3-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

In a 100-mL flask,(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(Example 24, step 7, A) (384 mg, 0.71 mmol) was dissolved in isopropanol(15 mL) and purged argon. Phenylsilane (2 eq.) and Shenvi's catalyst(tris[(Z)-1-tert-butyl-4,4-dimethyl-3-oxo-pent-1-enoxy]manganese) (3%)was added into above reaction solution. An poxygen balloon was applied.The mixture was stirred at r.t. for one day. LC-MS shows products, stillstarting material. The reaction was quenched by adding aqueous 10%sodium thiosulfate solution. The reaction mixture was extracted usingethyl acetate. The organic layer was concentrated down, and purified viasilica column (eluting with 0-10% MeOH/DCM) to give(1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(polar product, MS (m/z) 573.3 [M+H]⁺, NMR HMBC, COSY, NOE studiesconfirmed the structure) and (1S,2R,3S,5S)-8-(benzyloxy)-3-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(non-polar, MS (m/z) MS (m/z) 573.3 [M+H]⁺).

Preparation of(1S,2R,4R,5S)-4,8-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(4 mg) was dissolved in toluene (0.2 mL), trifluoroacetic acid (0.4 mL)was added. The reaction was stirred at r.t. for 2 hours. The reactionwas concentrated down and purified via preparative HPLC, eluting 10-100%acetonitrile (0.1% TFA) in water (0.1% TFA) to give the title compound.MS (m/z) 467.2 [M+H]⁺. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.35 (s,1H), 8.40 (s, 1H), 6.87 (t, J=8.5 Hz, 2H), 4.71-4.43 (m, 4H), 4.36 (p,J=6.8 Hz, 1H), 3.88 (dd, J=9.2, 6.0 Hz, 1H), 3.49 (m, 1H), 1.87-1.69 (m,1H), 1.51-1.19 (m, 7H).

Preparation of(1S,2R,4R,5S)-8-(benzyloxy)-4-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

In a 50-mL flask,(1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(10 mg, 0.018 mmol) was dissolved in DMF (1 mL), then was cooled down to0° C. in ice-water bath. Sodium hydride (60%, 1.4 mg, 2 eq.) was addedinto above reaction solution. After 10 minutes, methyl iodide (dilutedwith DCM to 100 times dilute, 0.11 mL, 1 eq.) was added. The mixture wasstirred at 0° C. for 30 minutes. LC-MS showed bis-Me product, major wasmono-Me product. The reaction was quenched by adding aqueous saturatedsodium bicarbonate solution. The reaction mixture was extracted usingethyl acetate. The organic layer was concentrate down, and purified viapreparative HPLC, eluting 10-100% acetonitrile (0.1% TFA) in water (0.1%TFA) to give the titled compound. MS (m/z) 571.3 [M+H]⁺.

Preparation of(1S,2R,4R,5S)-8-hydroxy-4-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C33)

(1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(4 mg) was dissolved in toluene (0.2 mL), trifluoroacetic acid (0.4 mL)was added. The reaction was stirred at r.t. for 2 hours. The reactionwas concentrated down and purified via preparative HPLC, eluting 10-100%acetonitrile (0.1% TFA) in water (0.1% TFA) to give to 1.6 mg the titlecompound. MS (m/z) 481.2 [M+H]⁺. ¹H NMR (400 MHz, Acetonitrile-d3) δ10.33 (s, 1H), 8.42 (d, J=8.2 Hz, 1H), 6.87 (t, J=8.5 Hz, 2H), 4.76-4.46(m, 4H), 3.45 (dd, J=9.0, 5.4 Hz, 2H), 3.30 (s, 3H), 1.90-1.74 (m, 2H),1.55-1.21 (m, 7H).

Example 34: Preparation of(1S,2R,4S,5S)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C34)

Preparation of(1S,2R,4S,5S)-8-(benzyloxy)-4-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

In a 50-mL flask,(1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(28 mg, 0.05 mmol) was dissolved in DCM (1.5 mL), then was cooled downto 0° C. in ice-water bath. Bis(2-methoxyethyl)aminosulfur trifluoride(50% in toluene, 2.7 M, 0.037 mL, 2 eq.) was added into above reactionsolution. The mixture was stirred at 0° C. for 30 minutes. LC-MS showedfluorination product and elimination product. The reaction was quenchedby adding aqueous saturated sodium bicarbonate solution. The reactionmixture was extracted using ethyl acetate. The organic layer wasconcentrate down, tried purification via normal phase silica column andpreparative HPLC, no separation. The mixture was dissolved in acetone (4mL) and water (0.5 mL) mixture, cooled down to 0° C. in ice-water bath.4-Methylmorpholine N-oxide (50% in water, 0.017 mL, 1.5 eq.) was slowlyadded into above reaction solution. Then 2.5% osmium tetroxide (0.023mL, 4% eq.) was added. The mixture was stirred at 0° C. and warm up tor.t. for 2 days. The reaction was quenched by adding aqueous 10% sodiumsulfite solution. The reaction mixture was extracted using ethylacetate. The organic layer was concentrate down, and purified viapreparative HPLC, eluting 10-100% acetonitrile (0.1% TFA) in water (0.1%TFA), collected the non-polar product to give(1S,2R,4S,5S)-8-(benzyloxy)-4-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(non-polar). MS (m/z) 559.3 [M+H]⁺.

Preparation of(1S,2R,4S,5S)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C34)

(1S,2R,4S,5S)-8-(benzyloxy)-4-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(8 mg) was dissolved in toluene (0.2 mL), trifluoroacetic acid (0.4 mL)was added. The reaction was stirred at r.t. for 2 hours. The reactionwas concentrated down and purified via preparative HPLC, eluting 10-100%acetonitrile (0.1% TFA) in water (0.1% TFA) to give the title compound.MS (m/z) 469.2 [M+H]⁺. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.26 (s,1H), 8.41 (s, 1H), 7.01-6.75 (m, 2H), 5.11-4.92 (m, 1H), 4.91-4.81 (m,2H), 4.66-4.59 (m, 2H), 3.49-3.34 (m, 1H), 2.39-2.23 (m, 1H), 1.95-1.79(m, 1H), 1.51, 1.30 (m, 1H), 1.45 (dd, J=7.1, 2.0 Hz, 3H), 1.35 (dd,J=7.2, 2.9 Hz, 3H).

Example 35: Preparation of(1S,2R,5S)-4,4-difluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:(C35)

Preparation of(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-4,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

In a 50-mL flask,(1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(127 mg, 0.228 mmol) was dissolved in DCM (3 mL), then was cooled downto 0° C. in ice-water bath. Dess-Martin periodinane (194 mg, 2 eq.) wasadded into above reaction solution. The mixture was stirred at 0° C. andwarm up to room temperature for 2 hours. The reaction was quenched byadding aqueous 10% sodium thiosulfate solution. The reaction mixture wasextracted using ethyl acetate. The organic layer was concentrated down,purified via silica column (eluting with 0-10% MeOH/DCM) to give(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-4,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(93 mg). MS (m/z) 555.3 [M+H]⁺.

Preparation of(1S,2R,5S)-8-(benzyloxy)-4,4-difluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

In a 50-mL flask,(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-4,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(110 mg, 0.2 mmol) was dissolved in DCM (5 mL), then was cooled down to0° C. in ice-water bath. Bis(2-methoxyethyl)aminosulfur trifluoride (50%in toluene, 2.7 M, 0.147 mL, 2 eq.) was added into above reactionsolution. The mixture was stirred at 0° C., and warmed up to roomtemperature overnight. The reaction was quenched by adding aqueoussaturated sodium bicarbonate solution. The reaction mixture wasextracted using ethyl acetate. The organic layer was concentrated downand purified via silica column (eluting with 0-10% MeOH/DCM) to give(1S,2R,5S)-8-(benzyloxy)-4,4-difluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 577.2 [M+H]⁺.

Preparation of(1S,2R,5S)-4,4-difluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C35)

(1S,2R,5S)-8-(benzyloxy)-4,4-difluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(25 mg) was dissolved in toluene (0.5 mL) and trifluoroacetic acid (2mL) was added. The reaction was stirred at r.t. for 2 hours. Thereaction was concentrated down and purified via preparative HPLC,eluting 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give thetitle compound. MS (m/z) 487.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.47(s, 1H), 10.29 (t, J=5.8 Hz, 1H), 8.24 (s, 1H), 7.31-7.16 (m, 2H), 5.76(s, 1H), 5.07 (d, J=15.2 Hz, 1H), 4.91 (dq, J=15.0, 7.2 Hz, 1H), 4.76(d, J=15.2 Hz, 1H), 4.57 (d, J=5.8 Hz, 2H), 3.21 (t, J=8.3 Hz, 1H), 2.83(ddd, J=32.9, 16.3, 10.1 Hz, 2H), 1.33 (dd, J=7.0, 3.1 Hz, 6H).

Example 36: Preparation of(1S,2R,5S)-3-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:(C36)

Preparation of(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-3,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

In a 25-mL flask,(1S,2R,3S,5S)-8-(benzyloxy)-3-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(16 mg, 0.028 mmol) was dissolved in DCM (1 mL), then was cooled down to0° C. in ice-water bath. Dess-Martin Periodinane (11 mg, 2 eq.) wasadded into above reaction solution. The mixture was stirred at 0° C. andwarm up to room temperature for 2 hours. The reaction was quenched byadding aqueous 10% sodium thiosulfate solution. The reaction mixture wasextracted using ethyl acetate. The organic layer was concentrated down,purified via silica column (eluting with 0-10% MeOH/DCM) to give(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-3,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 555.3 [M+H]⁺.

Preparation of(1S,2R,5S)-8-(benzyloxy)-3-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

In a 50-mL flask,(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-3,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(12 mg, 0.2 mmol) was dissolved in DCM (2 mL), then was cooled down to0° C. in ice-water bath. Bis(2-methoxyethyl)aminosulfur Trifluoride (50%in toluene, 2.7 M, 0.018 mL, 2 eq.) was added into above reactionsolution. The mixture was stirred at 0° C., and warmed up to roomtemperature for 3 hours. LC-MS showed elimination product and di-Fproduct. The reaction was quenched by adding aqueous saturated sodiumbicarbonate solution. The reaction mixture was extracted using ethylacetate. The organic layer was concentrated down, and purified viapreparative HPLC, eluting 10-100% acetonitrile (0.1% TFA) in water (0.1%TFA) to give(1S,2R,5S)-8-(benzyloxy)-3-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 557.3 [M+H]⁺.

Preparation of(1S,2R,5S)-3-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C36)

(1S,2R,5S)-8-(benzyloxy)-3-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(6 mg) was dissolved in toluene (0.2 mL) and trifluoroacetic acid (0.5mL) was added. The reaction was stirred at r.t. for 2 hours. Thereaction was concentrated down and purified via preparative HPLC,eluting 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give tothe title compound. MS (m/z) 467.2 [M+H]⁺. ¹H NMR (400 MHz,Acetonitrile-d3) δ 10.20 (s, 1H), 8.43 (s, 1H), 6.87 (t, J=8.5 Hz, 2H),5.70-5.48 (m, 1H), 5.32-5.17 (m, 1H), 5.00 (d, J=14.8 Hz, 1H), 4.78-4.57(m, 3H), 4.22-4.08 (m, 1H), 1.52 (dd, J=6.9, 3.0 Hz, 3H), 1.37 (d, J=7.2Hz, 3H).

Example 37: Preparation of(1S,2R,5S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C37)

To a solution of(1S,2R,5S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(10.2 mg, 0.023 mmol) in EtOH (5 mL), was added PtO₂ (2 mg, 0.009 mmol).The reaction was stirred at rt under H₂ balloon for 2 h. The reactionmixture was filtered through celite, the filtrate was concentrated downand the residue was purified by reverse phase HPLC, eluting with 5-100%acetonitrile in water to give the desired product. MS (m/z): 433.11[M+H]⁺. ¹H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.51-7.38 (m, 1H),6.97 (q, J=10.0, 9.5 Hz, 2H), 4.78 (d, J=14.3 Hz, 1H), 4.65 (s, 4H),3.57 (s, 1H), 2.05 (dd, J=15.0, 7.6 Hz, 1H), 1.82 (dd, J=15.1, 9.4 Hz,1H), 1.62 (d, J=12.2 Hz, 2H), 1.40 (d, J=7.0 Hz, 3H), 1.33 (d, J=6.7 Hz,3H).

Example 38: Preparation of(1S,2R,4R,5S)—N-(2,4-difluorobenzyl)-4,5-difluoro-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C38)

Step 1: Synthesis of(1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dihydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(15A)

(1S,2R,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(11A, 190 mg, 0.36 mmol) in 3 mL acetone and 0.45 mL water was cool to0° C. To it was added 4-methylmorpholine n-oxide (50% in water, 0.076ml, 0.36 mmol) and osmium tetroxide (2.5% in t-BuOH, 0.15 ml, 0.0014mmol). The reaction was stirred at room temperature for 2 days. Added10% Sodium sulfite aqueous solution (3 mL) to reaction and stirred for15 minutes. Extracted it with ethyl acetate three times. Combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered and concentrated to dryness. The residue was purified by silicagel chromatography eluting with methanol in dichloromethane to affordthe title product. Both hydroxy stereocenter were arbitrarily assigned.MS (m/z) 555.300 [M+H]⁺.

Step 2: Synthesis of(1S,2R,4R,5S)—N-(2,4-difluorobenzyl)-4,5-difluoro-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C38)

(1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dihydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(10 mg, 0.018 mmol) in dichloromethane (2 mL) was cooled to 0° C. underargon. To it was added Deoxo-fluoro (50% in toluene, 0.02 ml, 0.054mmol). The resulting mixture was stirred at 0° C. for three hours. Thereaction mixture was diluted with dichloromethane, cooled in anice/water bath and quenched by dropwise addition of saturated aqueoussodium bicarbonate. The resulting mixture was stirred for 20 minutes,added more saturated aqueous sodium bicarbonate until no more bubbling.The organic layer was separated, dried over magnesium sulfate and thesolvent removed under reduced pressure. The residue was purified byRP-HPLC eluting with acetonitrile/water (with 0.1% TFA) to afford(1S,2R,4R,5S)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-difluoro-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamidewhich was dissolved in 0.5 ml of Toluene and 0.5 ml of TFA. The reactionwas stirred at room temperature for one hour. The solvent removed underreduced pressure and the residue was purified by RP-HPLC eluting withacetonitrile/water (with 0.1% TFA) to afford the title product. MS (m/z)469.200 [M+H]⁺. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.32 (s, 1H), 8.33(s, 1H), 7.43 (q, J=9.1, 8.4 Hz, 1H), 7.00-6.95 (m, 2H), 4.82 (s, 2H),4.69 (s, OH), 4.60 (d, J=6.0 Hz, 2H), 4.37 (dq, J=8.5, 4.4 Hz, 1H), 4.19(dd, J=14.2, 7.9 Hz, 1H), 3.45 (t, J=7.3 Hz, 1H), 3.39-3.31 (m, 1H),2.29-2.06 (m, 2H), 1.20 (d, J=6.5 Hz, 3H).

Example 39: Preparation of(1S,2R,4S,5R)—N-(2,4-difluorobenzyl)-9-hydroxy-4,5-dimethoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C39)

Step 1: Synthesis of(1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-5-hydroxy-4-methoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamideand(1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dimethoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide

(1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dihydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(40 mg, 0.072 mmol) was dissolved in 2 ml of dry DMF and cooled to 0° C.using ice-water bath. Sodium hydride (3.8 mg of 60 weight % in oil,0.094 mmol) was added, and the mixture was stirred at 0° C. for 30minutes. To it was added iodomethane (0.0056 ml, 0.09 mmol), the mixturewas stirred at 0° C. for 10 min, quenched the reaction with saturatedammonium chloride aqueous solution and extracted it with ethyl acetatethree times. The combined organic extracts were washed with 5% lithiumchloride aqueous solution and brine, dried over magnesium sulfate,filtered and concentrated. The residue was purified by silica gelchromatography eluting with ethyl acetate in hexane to afford the titleproducts.

(1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-5-hydroxy-4-methoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide:(m/z): 569.300 [M+H]+.

(1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dimethoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide:(m/z): 583.300 [M+H]+.

Step 2: Synthesis of(1S,2R,4S,5R)—N-(2,4-difluorobenzyl)-9-hydroxy-4,5-dimethoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C39)

(1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dimethoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(10 mg, 0.017 mmol) was dissolved in 0.5 ml of toluene and 0.5 ml of TFAand stirred at room temperature for 20 minutes. The solvent removedunder reduced pressure and the residue was purified by RP-HPLC elutingwith acetonitrile/water (with 0.1% TFA) to afford the title product. MS(m/z) 493.200 [M+H]⁺. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 10.37 (s, 1H),8.32 (s, 1H), 7.49-7.38 (m, 1H), 6.97 (ddt, J=14.4, 8.4, 3.0 Hz, 2H),4.81 (d, J=15.0 Hz, 1H), 4.59 (d, J=6.2 Hz, 3H), 3.79 (dd, J=7.0, 3.6Hz, 2H), 3.46-3.37 (m, OH), 3.41 (s, 3H), 3.33 (s, 3H), 3.32 (d, J=13.2Hz, 1H), 3.19 (d, J=33.1 Hz, 1H), 3.20-3.08 (m, 1H), 2.18 (s, 1H), 1.94(d, J=2.5 Hz, 0H), 1.89-1.74 (m, OH), 1.18 (d, J=6.5 Hz, 3H).

Example 40: Preparation of(1S,2S)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C40)

Step 1: Synthesis of tert-butyl(tert-butoxycarbonyl)(prop-2-yn-1-yl)carbamate

To a stirred solution of prop-2-yn-1-amine (100 g, 181.65 mmol) inacetonitrile (2 L) was added Di-tert-butyl dicarbonate (991 g, 4541mmol) followed by DMAP (221.9 g, 181.65 mmol) portion wise at roomtemperature then stirred for 4 h at room temperature. After completionof the reaction, the reaction mixture was quenched with water andextracted with ethyl acetate. The combined organic layer was washed withbrine, dried over Na₂SO₄ and evaporated under reduced pressure to obtaincrude compound which was purified by silica gel column chromatographyeluting with ethyl acetate in hexane to obtain the title product as acolorless liquid. MS (m/z): 256.31[M+H]+.

Step 2: Synthesis of tert-butyl(R,Z)-(tert-butoxycarbonyl)(5-hydroxyhex-2-en-1-yl)carbamate

To a stirred solution of of tert-butyl(tert-butoxycarbonyl)(prop-2-yn-1-yl)carbamate (100 g, 390.6 mmol) inTHE (1 L) was added n-BuLi (1.6 M in hexane, 244.14 ml, 390.6 mmol)dropwise at −78° C. for 30 minutes. To this was added BF₃ etherate(119.7 g, 390.6 mmol) followed by a solution of (R)-2-methyloxirane(21.51 g, 390.6 mmol) in THE (0.5 L) dropwise. The reaction mixture wasstirred at this temperature for 4 h. After completion, the reactionmixture was quenched with saturated ammonium chloride solution andwater. The reaction mixture was extracted with ethyl acetate. Thecombined organic layer was washed with saturated NaHCO₃ solution andbrine, dried over Na₂SO₄ and evaporated to obtain crude which waspurified by silica gel column chromatography eluting with ethyl acetatein hexane to obtain tert-butyl(R)-(tert-butoxycarbonyl)(5-hydroxyhex-2-yn-1-yl)carbamate as acolorless liquid. Took 20 g (63.89 mmol), charged in a parr apparatus,and added 400 ml of ethyl acetate. Lindlar catalyst (4.4 g) was addedunder inert atmosphere followed by quinoline and hydrogenated under 30Psi at room temperature for 16 h. After completion, the reaction mixturewas filtered through a pad of celite. The celite pad was washed withethyl acetate. The filtrate was washed with 1 N HCl and concentratedunder reduced pressure to obtain crude which was purified by silica gelcolumn chromatography eluting with ethyl acetate in hexane to obtain thetitle product. MS (m/z): 316.29 [M+H]+.

Step 3: Synthesis of (R,Z)-6-aminohex-4-en-2-ol hydrochloride

A solution of tert-butyl(R,Z)-(tert-butoxycarbonyl)(5-hydroxyhex-2-en-1-yl)carbamate (14 g,44.44 mmol) and 4 M HCl in dioxane (210 ml) was stirred at roomtemperature for 1 h. After completion, the reaction mixture wasconcentrated under reduced pressure and crude was washed with diethylether, filtered, and dried under vacuum to afford the title product. MS(m/z): 116.3 [M+H]+.

Step 4: Synthesis of tert-butyl (R,Z)-(5-hydroxyhex-2-en-1-yl)carbamate

To a stirred solution of (R,Z)-6-aminohex-4-en-2-ol hydrochloride (2 g,13.2 mmol) in 30 ml of DCM was added di-tert-butyl dicarbonate (4.3 g,19.8 mmol) followed by triethylamine (5.52 ml, 39.6 mmol) at roomtemperature. The reaction mixture was stirred for overnight andconcentrated to dryness. The crude compound was purified by silica gelcolumn chromatography eluting with ethyl acetate in hexane to obtain thetitle product. ¹H NMR (400 MHz, Chloroform-d) δ 5.59 (dq, J=10.4, 5.4Hz, 2H), 4.67 (s, 1H), 3.94-3.78 (m, 2H), 3.71 (dd, J=15.0, 5.0 Hz, 1H),2.44-2.18 (m, 2H), 1.46 (s, 9H), 1.25 (d, J=6.3 Hz, 3H).

Step 5: Synthesis of methyl(S,Z)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(6-((tert-butoxycarbonyl)amino)hex-4-en-2-yl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate(26E)

Prepared in a manner similar to methyl(R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(pent-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(7A) using methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylateand tert-butyl (R,Z)-(5-hydroxyhex-2-en-1-yl)carbamate instead of methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylateand (2S)-pent-4-en-2-ol. MS (m/z): 741.400 [M+H]+.

Step 6: Synthesis of(S,Z)-1-((6-aminohex-4-en-2-yl)amino)-3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid hydrochloride (26F)

To a solution of Methyl(S,Z)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(6-((tert-butoxycarbonyl)amino)hex-4-en-2-yl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate(5.4 g, 7.29 mmol) in 140 ml of THF/MeOH/H₂O (3/2/1) was added lithiumhydroxide (698 mg, 29.2 mmol). The reaction mixture was stirred at 60°C. for 2 hours. LCMS showed high conversion to the carboxylic acid. Thereaction mixture was diluted with ethyl acetate, acidified to pH ˜4 with1 N HCl. Organic layer was washed with brine, dried over sodium sulfate,filtered and concentrated to afford(S,Z)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(6-((tert-butoxycarbonyl)amino)hex-4-en-2-yl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid which was dissolved in 50 ml of DCM, treated with 4 N HCl in1,4-dioxane (7.3 mL) at room temperature for overnight, concentrated todryness. High vacuum dried to afford the title product. MS (m/z):527.300 [M+H]+.

Step 7: Synthesis of(S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecine-11-carboxamide

(S,Z)-1-((6-aminohex-4-en-2-yl)amino)-3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid hydrochloride (5.29 g, 8.8 mmol) was dissolved in 500 ml of DCM. Toit was added EDCI.HCl (2.5 g, 13.2 mmol), HOAt (1.8 g, 13.2 mmol)followed by N,N-diisopropylethylamine (7.69 ml, 44.1 mmol). The reactionmixture was stirred at room temperature for 10 minutes, washed withwater and brine. The organic layer was separated, dried over magnesiumsulfate, filtered and concentrated. The residue was purified by silicagel chromatography eluting with EtOAc/hexane to afford the titleproduct. MS (m/z): 509.300 [M+H]+.

Step 8: Synthesis of(1R,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(26H) and(1S,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide

Prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F) using(S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecine-11-carboxamideinstead of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7E). After silica gel chromatography eluting with ethyl acetate inhexane to afford two products:

Peak 1:(1R,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide:MS (m/z): 521.300 [M+H]+.Peak 2:(1S,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide:MS (m/z): 521.300 [M+H]+.

Step 9: Synthesis of(1S,2S)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C40)

Prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11carboxamide (C8) using(1S,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamideinstead of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F). MS (m/z): 433.200 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d₃) δ11.45 (s, 1H), 10.40 (s, 1H), 8.29 (s, 1H), 7.49-7.38 (m, 1H), 7.04-6.91(m, 2H), 5.12 (d, J=14.1 Hz, 1H), 4.80 (d, J=14.2 Hz, 1H), 4.59 (d,J=5.9 Hz, 2H), 4.21 (dt, J=13.8, 4.7 Hz, 1H), 3.57 (p, J=7.2 Hz, 1H),3.02 (ddd, J=14.1, 10.1, 4.2 Hz, 1H), 1.97 (p, J=2.5 Hz, 3H), 1.84-1.70(m, 1H), 1.71-1.54 (m, 2H), 1.50-1.25 (m, 1H), 1.12 (d, J=7.0 Hz, 3H).

Example 41: Preparation of(1S,2S,Z)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C41)

Prepared in a manner similar to(2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11carboxamide (C7) using(1S,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamideinstead of(1S,2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F). MS (m/z): 431.200 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d₃) δ10.37 (s, 1H), 8.35 (s, 1H), 7.50-7.39 (m, 1H), 6.97 (ddt, J=12.9, 8.4,3.0 Hz, 2H), 5.89-5.77 (m, 1H), 5.62 (ddt, J=11.8, 4.3, 1.8 Hz, 1H),5.14 (d, J=13.8 Hz, 1H), 4.94 (d, J=18.1 Hz, 1H), 4.68-4.57 (m, 3H),3.55-3.38 (m, 2H), 2.26 (dt, J=16.1, 8.4 Hz, 1H), 1.97-1.86 (m, 1H),1.15 (d, J=7.0 Hz, 3H).

Example 42: Preparation of(1R,2S)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C42)

Prepared in a manner similar to(1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11carboxamide (C8) using(1R,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamideinstead of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F). MS (m/z): 433.200 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ10.38 (s, 1H), 8.35 (s, 1H), 7.44 (td, J=9.2, 8.8, 6.5 Hz, 1H),7.03-6.91 (m, 2H), 4.86 (d, J=14.5 Hz, 1H), 4.78 (d, J=14.5 Hz, 1H),4.60 (d, J=5.8 Hz, 2H), 4.15 (ddd, J=14.1, 7.4, 5.2 Hz, 1H), 3.14-3.02(m, 2H), 1.96-1.91 (m, 1H), 1.77 (dd, J=16.7, 7.1 Hz, 1H), 1.71-1.57 (m,1H), 1.45 (q, J=10.3 Hz, 2H), 1.17 (d, J=6.5 Hz, 3H).

Example 43: Preparation of(1R,2S,Z)—N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(C43)

Prepared in a manner similar to(2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11carboxamide (C7) using(1R,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamideinstead of(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide(7F). MS (m/z): 431.200 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d₃) δ10.41 (s, 1H), 8.44 (s, 1H), 7.44 (td, J=8.8, 6.5 Hz, 1H), 6.97 (ddt,J=10.8, 8.2, 3.0 Hz, 2H), 5.79-5.63 (m, 2H), 5.00-4.88 (m, 2H),4.69-4.57 (m, 3H), 3.61 (p, J=6.8 Hz, 1H), 3.58-3.48 (m, 1H), 2.42 (dd,J=15.5, 7.1 Hz, 1H), 2.10 (ddd, J=14.7, 8.4, 5.5 Hz, 1H), 1.29 (d, J=7.1Hz, 3H).

Example 44: Preparation of(2S,5S)—N-(2,4-difluorobenzyl)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C44)

Synthesis of3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid

Prepared in a manner similar to3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid (12) in example 6 using methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylateinstead of methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate.MS (m/z): 530.200[M+H]⁺.

Synthesis of tert-butyl(S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)carbamate

A reaction mixture of3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid (200 mg, 0.378 mmol), (2S)-but-3-en-2-amine hydrochloride (61 mg,0.567 mmol), HATU (172 mg, 0.453 mmol) and HOAt (61.7 mg, 0.453 mmol) in10 ml of DMF was cooled to 0° C. DIPEA (0.2 ml, 1.13 mmol) was addeddropwise. The reaction mixture was allowed to stir for 10 minutes, andthen poured into water. Extracted it with ethyl acetate three times.Combined organic layers were washed with 5% lithium chloride aqueoussolution and brine. The organic layer was dried over MgSO₄ andconcentrated under vacuum. The residue was purified by silica gel columnchromatography. MS (m/z) 583.300 [M+H]+.

Synthesis of tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)((S)-1-hydroxybut-3-en-2-yl)carbamate

Tert-butyl(S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)carbamate(430 mg, 0.738 mmol) and tetrabutyl ammonium bromide (476 mg, 1.48 mmol)was charged to a round bottom flask then acetonitrile (20 ml, degassedimmediately prior to use by bubbling through argon) followed by(R,R)-DACH naphthyl Trost ligand (58.4 mg, 0.0738 mmol) andtris(dibenzylideneacetone)dipalladium-chloroform adduct (22.9 mg, 0.0221mmol). The solution was stirred under argon at room temperature for 20minutes. Butadiene monoxide (0.149 ml, 1.85 mmol) was added. Thereaction mixture was stirred at room temperature for 2 hours. Thereactant mixture was concentrated in vacuo and purified by columnchromatography eluting with ethyl acetate in hexane to afford the titleproduct. MS (m/z) 653.300 [M+H]⁺

Synthesis of(S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)(tert-butoxycarbonyl)amino)but-3-en-1-ylacetate

Tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)((S)-1-hydroxybut-3-en-2-yl)carbamate(280 mg, 0.429 mmol) was dissolved in 14 ml of pyridine. To it was addedDMAP (105 mg, 0.858 mmol) and acetic anhydride (0.40 ml, 4.29 mmol). Thereaction was heated to 60° C. for 2 days, cooled to room temperature,and concentrated to dryness. The reaction mixture was partitionedbetween ethyl acetate and 1 N HCl, washed organic phase with more 1 NHCl, then saturated aqueous NaHCO₃ and brine. Dried organic phase overMgSO₄, filtered and concentrated in vacuo. Purified by Silica gel columnchromatography eluting with ethyl acetate in hexane to afford the titleproduct. MS (m/z) 695.400 [M+H]⁺.

Synthesis of(S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)amino)but-3-en-1-ylacetate

(S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)(tert-butoxycarbonyl)amino)but-3-en-1-ylacetate (202 mg, 0.29 mmol) was dissolved in 4 ml of DCM, to it wasadded hydrogen chloride, 4.0 M solution in 1,4-dioxane (0.73 ml, 2.9mmol). It was stirred at room temperature for 2 hours. The reactionmixture was concentrated in vacuo and high vacuum dried to afford thetitle product. MS (m/z) 595.300 [M+H]⁺.

Synthesis of(S)-2-(5-(benzyloxy)-3-((S)-but-3-en-2-yl)-7-((2,4-difluorobenzyl)carbamoyl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazin-1-yl)but-3-en-1-ylacetate

Prepared in a manner similar to5-(benzyloxy)-3-((S)-but-3-en-2-yl)-1-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamidein example 24 using(S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)amino)but-3-en-1-ylacetate instead of3-(Benzyloxy)-N2-((S)-but-3-en-2-yl)-1-(but-3-en-2-ylamino)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide.MS (m/z) 607.300 [M+H]⁺.

Synthesis of((2S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate

Prepared in a manner similar to(1R,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidein example 24 using(S)-2-(5-(benzyloxy)-3-((S)-but-3-en-2-yl)-7-((2,4-difluorobenzyl)carbamoyl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazin-1-yl)but-3-en-1-ylacetate instead of5-(Benzyloxy)-3-((S)-but-3-en-2-yl)-1-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide.MS (m/z) 579.300 [M+H]⁺.

Synthesis of(2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

((2S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate (46 mg, 0.79 mmol) was dissolved in 2 ml of methanol. To it wasadded potassium carbonate (22 mg, 0.16 mmol). The reaction was stirredat room temperature for 10 minutes, then partitioned between ethylacetate and water. The organic layer was separated, washed with brine,dried over MgSO₄ and concentrated to dryness to afford the titleproduct. MS (m/z) 537.300 [M+H]⁺.

Synthesis of(2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(fluoromethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(xxH, 15 mg, 0.028 mmol) in DCM (2 mL) was cooled at 0° C. under argon.to it was added Deoxo-fluro (50% in toluene, 0.031 ml, 0.084 mmol). Theresulting mixture was stirred at 0° C. for 2 h. The reaction mixture wasdiluted with DCM, cooled in an ice/water bath and quenched by dropwiseaddition of saturated aqueous NaHCO₃. The resulting mixture was stirredfor 20 min, added more saturated aqueous NaHCO₃ and stirred for 10 minuntil no more bubbling. The organic layer was separated, dried overNa₂SO₄ and the solvent removed under reduced pressure. The residue waspurified by silica gel chromatography eluting with EtOAc/hexane toafford the title product. MS (m/z) 539.200[M+H]⁺.

Synthesis of(2S,5S)—N-(2,4-difluorobenzyl)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C44)

(2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(fluoromethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(11 mg, 0.02 mmol) was dissolved in 0.5 ml of toluene and 0.5 ml of TFAand stirred at room temperature for 3 hours. The solvent removed underreduced pressure and the residue was purified by RP-HPLC eluting withacetonitrile/water (with 0.1% TFA) to afford the title product. MS (m/z)449.200[M+H]⁺. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 10.19 (s, 1H), 8.47(s, 1H), 7.44 (td, J=9.2, 8.7, 6.4 Hz, 1H), 6.97 (ddt, J=11.1, 8.5, 3.0Hz, 2H), 5.83 (dt, J=11.8, 2.7 Hz, 1H), 5.39 (ddt, J=14.5, 12.0, 2.9 Hz,2H), 4.96 (d, J=14.4 Hz, 1H), 4.70-4.57 (m, 4H), 4.52 (d, J=5.5 Hz, 1H),4.10 (ddq, J=20.0, 5.7, 2.9 Hz, 1H), 1.36 (d, J=7.3 Hz, 3H).

Example 45: Preparation of(1S,2S,5S)—N-(2,4-difluorobenzyl)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C45)

(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(fluoromethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(10 mg, 0.19 mmol) was dissolved in 3 ml of ethanol and 3 ml of ethylacetate, and was sparged under an argon atmosphere. Palladium on carbon(10 wt %, wet) E101 NE/W (2 mg) was added and the mixture was spargedunder a hydrogen atmosphere (1 atm, balloon). The mixture was stirredvigorously for one hour and then sparged under an argon atmosphere. Itwas filtered through a pad of Celite®. The Celite® was washed withabsolute ethanol and the filtrate was concentrated to dryness. theresidue was purified by RP-HPLC to afford the title product. MS (m/z)451.200[M+H]⁺. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.31 (s, 1H), 8.41(s, 1H), 7.44 (td, J=9.2, 8.7, 6.3 Hz, 1H), 7.03-6.91 (m, 2H), 5.05-4.26(m, 7H), 3.62-3.51 (m, 1H), 2.13-2.00 (m, 1H), 1.84 (ddd, J=15.6, 8.0,4.1 Hz, 1H), 1.77-1.57 (m, 2H), 1.26 (d, J=6.8 Hz, 3H).

Example 46: Preparation of(1R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C46)

Step 1: Synthesis of3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid

To a suspension of methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(10.0 g, 17.8 mmol, 1 equiv.), prepared according to Example 24, step 3,in methanol (200 mL) and water (100 mL) was added lithium hydroxidemonohydrate (5.979 g, 142 mmol, 8 equiv.). The reaction mixture washeated to 50° C. for 18 h, diluted with water, and acidified with 1 NHCl (aq). The slurry was extracted with EtOAc (2×) and the combinedorganic phase was washed with brine, dried over Na₂SO₄, filtered, andconcentrated to afford3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid. MS (m/z) 547.82 [M+H]⁺.

Step 2: Synthesis of tert-butyl(S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)carbamate

To a solution of3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid (6.00 g, 11.0 mmol, 1 equiv.), (S)-but-3-en-2-amine hydrochloride(1.769 g, 16.4 mmol, 1.5 equiv.), and HOBt (2.221 g, 16.4 mmol, 1.5equiv.) in CH₂Cl₂ (120 mL) at 0° C. was added DIPEA (9.54 mL, 54.8 mmol,5 equiv.) and EDCI (3.151 g, 16.4 mmol, 1.5 equiv.). The reactionmixture was warmed to rt and left to stir for 18 h. The reaction mixturewas quenched with water and 1 M HCl and extracted with CH₂Cl₂ (3×). Thecombined organic phase was dried over Na₂SO₄, filtered, andconcentrated. The crude residue was purified by column chromatography(0-100% EtOAc/hexanes) and concentrated to afford tert-butyl(S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)carbamate.MS (m/z) 600.90 [M+H]⁺.

Step 3: Synthesis of tert-butyl(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-1-carboxylate

To a suspension of tert-butyl(S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)carbamate(2.20 g, 3.66 mmol, 1 equiv.) and cesium carbonate (4.77 g, 14.7 mmol, 4equiv.) in MeCN (55 mL) was added diiodomethane (0.59 mL, 7.33 mmol, 2equiv.). The reaction mixture was heated to 70° C. for 8 h and quenchedwith NH₄Cl (aq). The mixture was extracted with EtOAc (2×) and thecombined organic phase was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by column chromatography (0-100%EtOAc/hexanes) to afford tert-butyl(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-1-carboxylate.MS (m/z) 612.79 [M+H]⁺.

Step 4: Synthesis of(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

To a solution of tert-butyl(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-1-carboxylate(2.00 g, 3.26 mmol, 1 equiv.) in methanol (55 mL) was added 2 N aqueousNaOH (2.45 mL, 4.90 mmol, 1.5 equiv.). The reaction mixture was heatedto 40° C. for 1 h, quenched with 10% citric acid solution, and dilutedwith CH₂Cl₂. The phases were separated, and the aqueous phase wasextracted with CH₂Cl₂. The combined organic phase was dried over Na₂SO₄,filtered, and concentrated. The residue was suspended in 1:1EtOAc/hexanes and the precipitate was collected by filtration to afford(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide.MS (m/z) 512.96 [M+H]⁺.

Step 5: Synthesis of5-(benzyloxy)-3-((S)-but-3-en-2-yl)-1-(1-methoxyallyl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

To a solution of(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(0.122 g, 0.237 mmol, 1 equiv.) in acetonitrile (5 mL) was addedPd(OAc)₂ (0.0027 g, 0.012 mmol, 0.05 equiv.),1,3-bis(diphenylphosphino)propane (dppp) (0.0049 g, 0.012 mmol, 0.05equiv.), triethylamine (0.050 mL, 0.356 mmol, 1.5 equiv.), andmethoxyallene (0.100 mL, 1.19 mmol, 5 equiv.). The reaction mixture washeated to 100° C. for 20 min. Water and brine were added and the aqueousphase was extracted with EtOAc (2×). The combined organic phase wasdried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby column chromatography (0-100% EtOAc/hexanes) to provide5-(benzyloxy)-3-((S)-but-3-en-2-yl)-1-(1-methoxyallyl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide.MS (m/z) 583.00 [M+H]⁺.

Step 6: Synthesis of(1R,2R,5S)-8-(benzyloxy)-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a solution of5-(benzyloxy)-3-((S)-but-3-en-2-yl)-1-(1-methoxyallyl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(0.112 g, 0.192 mmol, 1 equiv.) in 1,2-dichloroethane (5 mL) was addedHoveyda-Grubbs II catalyst (0.024 g, 0.038 mmol, 0.2 equiv.). Thereaction mixture was heated to 70° C. for 24 h and concentrated. Theresidue was purified by preparative HPLC (column, Gemini 10μ C18 110A,AXI/; 250×21.2 mm) eluting 5-100% acetonitrile (0.1% TFA) in water (0.1%TFA) over 20 minutes. Combined fractions were lyophilized to afford(1R,2R,5S)-8-(benzyloxy)-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 554.98.

Step 7: Synthesis of(R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C46)

To a solution of(1R,2R,5S)-8-(benzyloxy)-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(0.0455 g, 0.0821 mmol, 1 equiv.) in DMF (2 mL) was added lithiumchloride (0.0348 g, 0.821 mmol, 10 equiv.). The reaction mixture washeated to 100° C. for 1 h and filtered. The filtrate was purified bypreparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2 mm)eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20minutes. Combined fractions were lyophilized to afford(1R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 465.02 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (t, J=5.8 Hz,1H), 8.21 (s, 1H), 7.20 (t, J=8.6 Hz, 2H), 5.76 (dt, J=12.1, 2.3 Hz,1H), 5.55 (dt, J=12.0, 2.4 Hz, 1H), 5.29-5.17 (m, 2H), 5.06 (d, J=14.6Hz, 1H), 4.75 (d, J=14.6 Hz, 1H), 4.57 (d, J=5.8 Hz, 2H), 3.39 (s, 3H),1.28 (d, J=7.2 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.25 (ddd,J=15.5, 9.3, 6.2 Hz), −112.45-−112.69 (m).

Example 47: Preparation of(1R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C47)

Step 1: Synthesis of(R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide)

To a solution of(1R,2R,5S)-8-(benzyloxy)-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(0.008 g, 0.0144 mmol, 1 equiv.), prepared according to Example 46, inmethanol (1 mL) was added platinum(IV) oxide (0.0003 g, 0.0014 equiv.0.1 equiv). The reaction mixture was evacuated and backfilled withhydrogen gas (2×), sparged with hydrogen gas for 5 min, and left to stirunder hydrogen balloon atmosphere for 1 h. The reaction mixture wasfiltered, concentrated, and purified by preparative HPLC (column, Gemini10μ C18 110A, AXI/; 250×21.2 mm) eluting 5-100% acetonitrile (0.1% TFA)in water (0.1% TFA) over 20 minutes. Combined fractions were lyophilizedto afford(1R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 467.07 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (t, J=5.9 Hz,1H), 8.25 (s, 1H), 7.20 (t, J=8.6 Hz, 2H), 4.69-4.59 (m, 2H), 4.59-4.49(m, 2H), 4.45 (s, 1H), 4.44-4.35 (m, 1H), 3.53 (s, 3H), 1.91-1.72 (m,3H), 1.34-1.22 (m, 1H), 1.17 (d, J=6.7 Hz, 3H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ−109.32 (ddd, J=15.5, 9.4, 6.4 Hz), −112.55 (t, J=7.2 Hz).

Example 48: Preparation of(1S,5S)-8-hydroxy-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C48)

Step 1: Synthesis of(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-1-(2-methylbut-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

To a solution of(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(0.150 g, 0.293 mmol, 1 equiv.), prepared according to Example 46,(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamideand Pd(PPh₃)₄ (0.0338 g, 0.029 mmol, 0.1 equiv.) in THE (3 mL) and DMF(0.15 mL) was added methyl (2-methylbut-3-en-2-yl) carbonate (0.0633 g,0.439 mmol, 1.5 equiv.). The reaction mixture was heated to 60° C. for 2h and concentrated. The residue was purified by column chromatography(0-100% EtOAc/hexanes) and the pure fractions were collected andconcentrated to afford(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-1-(2-methylbut-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide.MS (m/z) 581.02 [M+H]⁺.

Step 2: Synthesis of(1S,5S)-8-(benzyloxy)-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a solution of (0.019 g, 0.033 mmol, 1 equiv.) in 1,2-dichloroethane(1 mL) was added Hoveyda-Grubbs II catalyst (0.004 g, 0.006 mmol, 0.2equiv.). The reaction mixture was sparged with Ar (g) for 10 min andheated to 75° C. for 18 h. The mixture was concentrated and purified bycolumn chromatography (0-100% EtOAc/hexanes) to afford(1S,5S)-8-(benzyloxy)-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 553.00 [M+H]⁺.

Step 3: Synthesis of(1S,5S)-8-hydroxy-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C49)

(1S,5S)-8-(benzyloxy)-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(0.011 g, 0.020 mmol, 1 equiv.) was dissolved in 1:1 TFA/toluene (2 mL)and stirred at rt for 5 h. The reaction mixture was concentrated,dissolved in MeCN, filtered, and purified by preparative HPLC (column,Gemini 10μ C18 110A, AXI/; 250×21.2 mm) eluting 5-100% acetonitrile(0.1% TFA) in water (0.1% TFA) over 20 minutes. Combined fractions werelyophilized to afford(1S,5S)-8-hydroxy-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 463.10 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (t, J=5.7 Hz,1H), 8.25 (s, 1H), 7.23-7.17 (m, 2H), 5.41 (td, J=11.8, 11.3, 2.9 Hz,1H), 5.33 (dd, J=12.4, 2.0 Hz, 1H), 5.29-5.18 (m, 1H), 5.06-4.98 (m,1H), 4.72 (d, J=14.5 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 1.49 (s, 3H), 1.28(d, J=7.2 Hz, 3H), 0.93 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−109.19(ddd, J=15.6, 9.3, 6.3 Hz), −112.52 (q, J=7.3, 5.9 Hz).

Example 49: Preparation of(1S,10R,13R)—N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-6-hydroxy-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide(C49a) and(1S,10R,13R)—N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-6-hydroxy-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide(C49b)

Step 1: Synthesis of methyl3-benzyloxy-1-(tert-butoxycarbonyl(1-methylallyl)aminol-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxo-pyridine-2-carboxylate

To a mixture of methyl3-benzyloxy-1-(tert-butoxycarbonylamino)-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxo-pyridine-2-carboxylate(8 g, 14.7 mmol) in THF (75 mL) at 0° C. was added but-3-en-2-ol (1.59g, 22.1 mmol), triphenyl phosphine (5.79 g, 22.1 mmol). Diisopropylazodicarboxylate (4.46 g, 22.1 mmol) was then added dropwise. Theresulting mixture was stirred at 0° C. for 5 minutes before it wasremoved from the cooling bath and stirred at room temperature for 2hours. The reaction was mixed with silica gel, concentrated and purifiedby normal phase chromatography. LCMS-ESI+ (m/z): calcd H+ forC31H33F2N3O7, Theoretical: 597.23, Found: 597.88.

Step 2: Synthesis of3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxo-pyridine-2-carboxylicacid

Methyl3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxo-pyridine-2-carboxylate(10 g, 16.7 mmol) was dissolved in a mixture of MeOH (96 mL), THE (48mL) and water (48 mL). Lithium hydroxide monohydrate (4.2 g, 41.96 mmol)was added. The resulting mixture was heated to 60° C. for 6 hrs. Thereaction was then cooled to rt, concentrated, residue was diluted withEtOAc, acidified to pH ˜4 with 1 N HCl, organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated to give alight pinkish solid. The resulting product was used directly in nextstep. LCMS-ESI+ (m/z): calcd H+ for C30H31F2N3O7, Theoretical: 583.21,Found: 583.87.

Step 3: Synthesis of tert-butylN-[3-benzyloxy-5-[(2,4-difluorophenyl)methylcarbamoyl]-2-[[(1R)-1-(hydroxymethyl)allyl]carbamoyl]-4-oxo-1-pyridyl]-N-(1-methylallyl)carbamate

The residue from previous step (7 g, 12.0 mmol) was dissolved in DCM (60mL) at room temperature. To this stirred mixture was added(2R)-2-aminobut-3-en-1-ol (1.57 g, 18.0 mmol) followed by EDCI. HCl(4.12 g, 21.6 mmol), HOAt (2.94 g, 21.6 mmol) and DIEA (6.2 g, 48 mmol).The newly formed mixture was stirred for one hour. The reaction was thendiluted with DCM, washed with 10% citric acid, brine, dried over sodiumsulfate, filtered and concentrated and used directly in next step.LCMS-ESI+ (m/z): calcd H+ for C34H38F2N4O7, Theoretical: 652.27, Found:653.03.

Step 4: Synthesis of3-benzyloxy-N5-[(2,4-difluorophenyl)methyl]-N2-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallylamino)-4-oxo-pyridine-2,5-dicarboxamide

Tert-butylN-[3-benzyloxy-5-[(2,4-difluorophenyl)methylcarbamoyl]-2-[[(1R)-1-(hydroxymethyl)allyl]carbamoyl]-4-oxo-1-pyridyl]-N-(1-methylallyl)carbamate(7.8 g, 12 mmol) was dissolved in DCM (70 mL) at room temperature andtreated with 4 N HCl in 1,4-dioxane (70 mL) at room temperature for 1hour. The reaction was concentrated, diluted with EtOAc, basified withsat. sodium bicarbonate slowly till no bubbling, then solid sodiumbicarbonate was added to saturate the aqeuous layer. Extracted withEtOAc, washed organic layer with brine, dried over sodium sulfate,filtered and concentrated to give a brownish oil. The resulting productwas used directly in next step. LCMS-ESI+ (m/z): calcd H+ forC29H30F2N4O5, Theoretical: 552.22, Found: 553.09.

Step 5: Synthesis of5-benzyloxy-N-[(2,4-difluorophenyl)methyl]-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

3-Benzyloxy-N5-[(2,4-difluorophenyl)methyl]-N2-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallylamino)-4-oxo-pyridine-2,5-dicarboxamide(1.57 g, 2.84 mmol) was dispensed in a mixture of DCE (5.3 mL) andacetonitrile (5.3 mL) at room temperature, paraformaldehyde (224 mg) wasadded. The resulting mixture was then heated to 88° C., a mixture ofAcOH (0.79 mL) and TFA (0.79 mL) was added in one portion quickly. Thereaction was sealed and stirred for 1 hr. The reaction was then cooledto room temperature, concentrated, redissolved in EtOAc, washed withsaturated sodium bicarbonate, brine, dried over sodium sulfate, filteredand concentrated to give a brownish oil. The residue was then dissolvedin DMF (5 mL) and treated with potassium carbonate (392 mg, 2.84 mmol)and benzyl bromide (485 mg, 2.84 mmol). The reaction was then heated at70° C. for 2 hours before it was cooled to room temperature, partitionedbetween EtOAc and water. The organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated, purified by normal phasechromatography. LCMS-ESI+ (m/z): calcd H+ for C30H30F2N4O5, Theoretical:564.22, Found: 565.02.

Step 6: Synthesis of5-benzyloxy-N-[(2,4-difluorophenyl)methyl]-3-[(1R)-1-(fluoromethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

5-Benzyloxy-N-[(2,4-difluorophenyl)methyl]-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(851 mg, 1.51 mmol) was dissolved in DCM (12.0 mL) at 0° C.Bis(2-methoxyethyl)aminosulfur trifluoride (1.33 g, 6.03 mmol) wasadded. The reaction was removed from cooling bath after addition andstirred at ambient for overnight. The reaction was then cooled to 0° C.and quenched with saturated sodium bicarbonate. Additional sodiumbicarbonate powder was added to saturate the mixture. The reaction wasextracted with DCM, washed with brine, dried over sodium sulfate,filtered and concentrated, purified by normal phase chromatography.LCMS-ESI+ (m/z): calcd H+ for C30H29F3N4O4, Theoretical: 566.21, Found:566.99.

Step 7: Synthesis of(1S,10R,13R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide

A solution of5-benzyloxy-N-[(2,4-difluorophenyl)methyl]-3-[(1R)-1-(fluoromethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(370 mg, 0.65 mmol) in DCE (9 mL) at room temperature was sparged withArgon. Hoveyda-Grubbs II catalyst HG-M720 (41 mg, 0.065 mmol) was added.The mixture was sparged for Argon for another 5 minutes and then wassealed and heated at 80° C. under nitrogen balloon for overnight. Thereaction was then cooled to room temperature, concentrated and purifiedby normal phase chromatography. ¹H NMR (400 MHz, CDCl3) δ 10.38 (t,J=6.0 Hz, 1H), 8.54 (s, 1H), 7.55-7.47 (m, 2H), 7.44-7.29 (m, 4H),6.89-6.76 (m, 2H), 5.83 (dt, J=10.8, 2.3 Hz, 1H), 5.62-5.45 (m, 3H),5.25 (d, J=10.5 Hz, 1H), 5.11 (d, J=14.6 Hz, 1H), 4.79-4.65 (m, 1H),4.65-4.62 (m, 2H), 4.62-4.46 (m, 1H), 4.26 (d, J=14.6 Hz, 1H), 3.77 (tp,J=6.6, 3.3 Hz, 1H), 1.41 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): calcd H+for C28H25F3N4O4, Theoretical: 538.18, Found: 539.09.

Step 8: Synthesis of(1S,10R,13R)—N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-6-hydroxy-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide

(1S,10R,13R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide(20 mg, 0.037 mmol) was treated with a mixture of DCM (1.5 mL) and TFA(1.5 mL) at room temperature for 2 hours. The reaction was concentrated,redissolved in DMF and purified by reverse phase prep HPLC. Absoluteconfiguration at C13 is not confirmed. ¹H NMR (400 MHz, Acetonitrile-d3)δ 10.15 (s, 1H), 8.39 (s, 1H), 7.44 (td, J=9.2, 8.8, 6.5 Hz, 1H),7.09-6.88 (m, 2H), 5.81 (dt, J=11.5, 2.3 Hz, 1H), 5.66-5.59 (m, 1H),5.54-5.41 (m, 1H), 5.13 (d, J=14.5 Hz, 1H), 4.80-4.55 (m, 5H), 3.87 (dp,J=10.1, 3.4 Hz, 1H), 1.37 (d, J=6.7 Hz, 3H). LCMS-ESI+ (m/z): calcd H+for C21H19F3N4O4, Theoretical: 448.14, Found: 449.10.

Step 9: Synthesis of(1S,10R,13R)—N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-6-hydroxy-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide

(1S,10R,13R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide(20 mg, 0.037 mmol) was dissolved in EtOH (20 mL) at room temperature.10% Pd/C (4 mg) was added, the reaction was degassed and flushed withnitrogen three times and then degassed and flushed with hydrogen threetimes before it was hydrogenated under hydrogen balloon for 1 hr. Thereaction was then degassed and flushed with Nitrogen, filtered throughCelite, concentrated and purified by reverse phase prep HPLC. Absoluteconfiguration at C13 is not confirmed. ¹H NMR (400 MHz, Acetonitrile-d3)δ 10.33 (s, 1H), 8.45 (s, 1H), 7.44 (td, J=9.2, 8.8, 6.5 Hz, 1H),7.06-6.86 (m, 2H), 4.79-4.39 (m, 7H), 3.63-3.58 (m, 1H), 1.95-1.82 (m,2H), 1.62 (dt, J=7.1, 3.5 Hz, 2H), 1.32 (d, J=7.2 Hz, 3H). LCMS-ESI+(m/z): calcd H+ for C21H21F3N4O4, Theoretical: 450.15, Found: 451.12.

Example 50: Preparation of(1S,2R,5R)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C50)

Synthesis of methyl3-benzyloxy-1-[(tert-butoxycarbonyl(1-methylallyl)amino]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylate

To methyl3-benzyloxy-1-(tert-butoxycarbonylamino)-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylate(10 g, 17.8 mmol) in THE (200 ml) at 0° C. was added but-3-en-2-ol (1.93g, 26.7 mmol), followed by the addition of Ph₃P (7.0 g, 26.7 mmol). ThenDIAD (5.4 g, 26.7 mmol) was added drop-wise over 5 min. The resultingreaction mixture was stirred at 0° C. for 5 min and then warmed up toroom temperature. the reaction was stirred at room temperature forovernight. Solvent was removed under vacuo and the resulting crudmaterial was purified by silica gel column to obtain the title compound.MS (m/z) 615.99 [M+H]⁺

Synthesis of3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylicacid

To methyl3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylate(1 Ig, 17.9 mmol) in MeOH (80 ml) was added aqueous LiOH solution (2.5N) (43 ml, 107 mmol). The reaction mixture was heated to 70° C. forovernight. Reaction mixture was concentrated carefully for removal ofMeOH. The residue was diluted and rinsed with some water and wasacidified with 1 N HCl to pH=3. EtOAc was added for extraction. Organicphase was separated. Aqueous layer was extracted with more EtOAc. Thecombined organic phases were washed with water and brine, dried overNa₂SO₄, filtered and concentrated to afford the title compound. Thecrude material was taken forward to next step. MS (m/z) 601.84 [M+H]⁺

Synthesis of tert-butylN-[3-benzyloxy-2-[[(1R)-1-(hydroxymethyl)allyl]carbamoyl]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]-1-pyridyl]-N-(1-methylallyl)carbamate

To3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylicacid (11.2 g, 18.6 mmol) in DMF (50 ml) was added DIEA (16.2 ml, 93.1mmol) followed by the addition of HATU (9.2 g, 24.2 mmol). After thereaction mixture was stirred at rt of 1 hour, (2R)-2-aminobut-3-en-1-ol;hydrochloride (2.9 g, 24.2 mmol) was added to the reaction mixture. 2 hlater, the reaction mixture was diluted with EtOAc and washed withaqueous LiCl. Aqueous layer was extracted with EtOAc (1×). Combinedorganic phases were washed with water (1×). Organic phase was dried withMgSO₄ and concentrated to afford the crude which was purified by silicagel chromatography to afford the title compound. MS (m/z) 670.86 [M+H]⁺

Synthesis of3-benzyloxy-N2-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallylamino)-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide

Tert-butylN-[3-benzyloxy-2-[[(1R)-1-(hydroxymethyl)allyl]carbamoyl]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]-1-pyridyl]-N-(1-methylallyl)carbamate(XX-3) (10 g, 14.9 mmol) was dissolved in DCM (50 ml) at rt. HCl (4 M indioxane) (11.2 mL, 44.7 mmol)) was added. The reaction mixture wasstirred for 24 h at r.t. LCMS shows reaction was done. So reactionmixture was then concentrated to dryness. The residue was thenpartitioned between EtOAc and aqueous NaHCO₃ solution. Aqueous layer wasextracted with EtOAc. Combined organic phases were washed with water,dried over Na2SO4, filtered and concentrated to afford the titlecompound. MS (m/z) 571.06 [M+H]⁺

Synthesis of5-hydroxy-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(2 g 4.06 mmol) in DMF was Added bromomethylbenzene

To3-benzyloxy-N2-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallylamino)-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide(XX-4) (0.89 g, 1.56 mmol) in 20 ml microwave reaction viral in CAN (5ml) and DCE (5 ml) was added paraformaldehyde (93.1 mg, 3.04 mmol), AcOH(0.5 mL), followed by the addition of TFA (0.5 mL). the viral was cappedafter addition and it was heated to 89° C. for overnight. LCMS showedcomplete reaction. The reaction mixture was diluted with EtOAc and waswashed with sat. aqueous NaHCO₃. Organic phase was dried with MgSO4 andsolvent was removed under vacuo to afford the crude material of titlecompound, crude was taken forward to next step. MS (m/z) 535.1 [M+H]⁺

Synthesis of[(2R)-2-[5-benzyloxy-1-(1-methylallyl)-4,6-dioxo-7-[(2,4,6-trifluorophenyl)methylcarbamoyl]-2H-pyrido[2,1-f][1,2,4]triazin-3-yl]but-3-enyl]acetate

To5-hydroxy-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(2 g, 4.06 mmol) in DMF was added bromomethylbenzene (XX-5) (2.08 g,12.2 mmol) and followed by the addition of POTASSIUM CARBONATE (2.93 g,21.2 mmol). The reaction mixture was stirred at 60° C. for overnight.Lcms showed complete reaction. The reaction mixture was diluted withEtOAc and was washed with sat. aqueous NaHCO₃. Organic phase was driedwith MgSO4 and solvent was removed under vacuo to afford the crudematerial. MS (m/z) 625 [M+H]⁺

Synthesis of5-benzyloxy-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

To the crude[(2R)-2-[5-benzyloxy-1-(1-methylallyl)-4,6-dioxo-7-[(2,4,6-trifluorophenyl)methylcarbamoyl]-2H-pyrido[2,1-f][1,2,4]triazin-3-yl]but-3-enyl]acetate (7.61 g, 12.2 mmol) in MeOH (100 ml) was added NaOH (1 N) (63ml, 63.3 mmol). The mixture was stirred at rt of 30 minutes. LCMS showedreaction was complete. Solvent was removed under vacuo, the resultingresidue was diluted in EtOAc and washed with H₂O. Organic phase wasdried with MgSO₄ and concentrated under vacuo. The resulting crudematerial was purified by silicone gel column to provide the titlecompound. MS (m/z) 583.01 [M+H]⁺

Synthesis of5-benzyloxy-3-[(1R)-1-(fluoromethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

At 0° C., to5-benzyloxy-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(XX-7) (0.82 g, 1.41 mmol) in DCM (8 ml) was added deoxo-fluor in tolune(2.7 N) (5.21 ml, 14.1 mmol), then the mixture was slowly warmed up tort and it was stirred for overnight. Reaction mixture was added to icedNaHCO₃ aqueous slowly, then extracted with DCM. DCM phase was dried withMgSO₄ and crude was purified by silicone gel column to afford the titlecompound. MS (m/z) 585.03 [M+H]⁺

Synthesis of(1S,10R,13R)-6-benzyloxy-10-(fluoromethyl)-13-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide

5-benzyloxy-3-[(1R)-1-(fluoromethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(XX-9) (0.41 g, 0.7 mmol) was dissolved in DEC (25 ml) and degassed byvacuum then refilled with N2 (×3) at rt. Then catalyst HG-II was addedinto the solution and flushed with argon 1.5 h with vented needle at 80°C. Afterwards, vented needle was removed and the reaction was stirredwith argon balloon at 80° C. for overnight. LCMS showed completereaction, solvent was removed under vacuo and the resulting residue waspurified by silicone gel column to afford the title compound (XX-9). MS(m/z) 556.94 [M+H]⁺

Synthesis of(1S,2R,5R)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C50)

To(1S,10R,13R)-6-benzyloxy-10-(fluoromethyl)-13-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide(80 mg, 0.144 mmol) in Toluene (2 ml) was added TFA (2 ml), the reactionmixture was stirred at room temperature for overnight. LCMS showedcomplete reaction. Solvent was removed under vacuo and resultingmaterial was purified by prep-HPLC to afford the title compound (51). MS(m/z) 467 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 10.19 (s, 1H), 8.57(s, 1H), 6.75-6.68 (m, 3H), 5.88 (dt, J=11.4, 2.3 Hz, 1H), 5.65 (dt,J=11.4, 3.5 Hz, 1H), 5.49 (dd, J=32.6, 3.1 Hz, 1H), 5.26 (d, J=14.6 Hz,1H), 4.84 (dd, J=9.9, 3.3 Hz, 1H), 4.77-4.66 (m, 3H), 4.67-4.55 (m, 2H),3.80 (dq, J=6.7, 3.4 Hz, 1H), 1.43 (d, J=6.7 Hz, 3H).

Example 51: Preparation of(1S,2R,5R)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C51)

(1S,10R,13R)-6-benzyloxy-10-(fluoromethyl)-13-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide(from Example 50) (520 mg, 0.93 mmol) was dissolved in EtOH (100 ml),then followed by the addition of Pd/C (10% Wt) (7.8 mg, 0.09 mmol). Thenthe mixture was vacuum and back filled with H₂ three times. The reactionwas stirred under H₂ overnight. LCMS showed complete reaction. Reactionmixture was filtered with Celite to remove Pd/C, and solvent was removedunder vacuo. The resulting crude material was purified by prep-HPLC toafford the title compound (XX). MS (m/z) 469.11 [M+H]⁺1H NMR (400 MHz,Chloroform-d) δ 10.37 (s, 1H), 8.61 (s, 1H), 6.82-6.59 (m, 2H),4.79-4.44 (m, 7H), 3.64-3.39 (m, 1H), 2.35-2.27 (m, 1H), 2.14-1.86 (m,1H), 1.71-1.61 (m, 2H), 1.38 (d, J=7.1 Hz, 3H).

Example 52: Preparation of(1S,2R,4S,5S)—N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C52)

Step 1: Preparation of(1S,2R,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

A solution of(1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(455 mg, 0.85 mmol), prepared according to Example 29, in isopropylalcohol (5 mL) was purged with Argon. To the solution of addedphenylsilane (189 mg, 1.75 mmol) andtris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (16 mg, 0.026mmol). The reaction mixture was stirred at rt under oxygen balloon forone day. Then the reaction was quenched by adding 10% sodium thiosulfatesolution and the mixture was extracted with EtOAc. The organic phase wasseparated and dried over MgSO₄, filtered, concentrated down and theresidue was purified by silica gel chromatography column, eluting with0-100% hexane/EtOAc to give title product. MS (m/z) 539.03 [M+H]+.

Step 2: Preparation of(1S,2R,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a solution of(1S,2R,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(20 mg, 0.037 mmol) in DCM (2 mL) was added deoxofluor solution intoluene (50%, 0.041 mL, 0.11 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 15 min and the reaction was quenched by adding sat.NaHCO₃ solution. The mixture was extracted with DCM, the organic phasewas separated and dried over MgSO₄, filtered, concentrated down andpurified by silica gel chromatography column (eluting with 0-100%hexane/EtOAc) to give the title compound. MS (m/z) 540.92 [M+H]+.

Step 3: Preparation of(1S,2R,4S,5S)—N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a solution of(1S,2R,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(13 mg, 0.024 mmol) in DCM (1 mL) was added TFA (1 mL). The reactionmixture was stirred at rt overnight. The reaction mixture wasconcentrated down, and the residue was purified by reverse phase HPLC,eluting with 5-100% acetonitrile in water to give title compound. MS(m/z) 451.12 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.45(td, J=8.5, 6.4 Hz, 1H), 7.04-6.90 (m, 2H), 5.13-5.03 (m, 1H), 5.03-4.91(m, 2H), 4.73 (d, J=15.0 Hz, 1H), 4.65 (s, 2H), 3.50-3.41 (m, 1H), 2.42(dt, J=15.8, 7.7 Hz, 1H), 2.01-1.84 (m, 1H), 1.52 (dd, J=7.1, 1.7 Hz,3H), 1.41 (dd, J=7.1, 2.7 Hz, 3H).

Example 53: Preparation of(1S,2R,4R,5S)—N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C53)

Step 1: Preparation of(1S,2R,4S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-4-ylbenzoate

To a solution of(1S,2R,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(36.0 mg, 0.067 mmol), prepared according to Example 52, in THE (2 mL)was added benzoic acid (24.5 mg, 0.201 mmol), diisopropylazodicarboxylate (40.6 mg, 0.201 mmol) and triphenyl phosphine (53 mg,0.201 mmol). The reaction mixture was stirred at rt for 3 h. Thereaction mixture was diluted with EtOAc, washed with sat. NaHCO₃, andextracted with EtOAc. The organic phase was dried over MgSO₄, filtered,concentrated down and the residue was purified by silica gelchromatography, eluting with 0-100% hexane/EtOAc, to give the titleproduct. MS (m/z) 643.02 [M+H]+.

Step 2: Preparation of(1S,2R,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a solution of(1S,2R,4S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-4-ylbenzoate (15 mg, 0.023 mmol) in MeOH (2 mL) and water (0.5 mL), wasadded LiOH.H₂O (2.80 mg, 0.117 mmol). The reaction mixture was stirredat rt overnight. The reaction mixture was concentrated down. The residuewas washed with sat. NaHCO₃, extracted with EtOAc, dried over MgSO₄,filtered, concentrated down and used in next step without purification.

Steps 3-4: Preparation of(1S,2R,4R,5S)—N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,4R,5S)—N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas prepared in a similar way as Example 52, except that(1S,2R,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas used instead of(1S,2R,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 451.11 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H),7.46 (dd, J=8.7, 6.4 Hz, 1H), 7.04-6.90 (m, 2H), 5.13-5.03 (m, 1H),5.03-4.91 (m, 2H), 4.72 (d, J=15.0 Hz, 1H), 4.65 (s, 2H), 3.46 (d, J=8.4Hz, 1H), 2.42 (dt, J=15.7, 7.9 Hz, 1H), 2.00-1.84 (m, 2H), 1.52 (dd,J=7.0, 1.7 Hz, 3H), 1.41 (dd, J=7.0, 2.7 Hz, 3H).

Example 54: Preparation of(1S,2R,5S)—N-(2,4-difluorobenzyl)-4,4-difluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C54)

Step 1: Preparation of(1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-4,7,9-trioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a solution of(1S,2R,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(60 mg, 0.11 mmol) in DCM (2.0 mL), was added Dess-Martin periodinane(94.5 mg, 0.223 mmol) at 0° C. Then the reaction mixture was stirred atrt for 3 h. The reaction mixture was quenched by adding 1N NaS₂SO₃, themixture was washed by Sat. NaHCO₃ and extracted with DCM. The organicphase was separated, dried over MgSO₄, filtered, concentrated down andthe residue was purified by silica gel chromatography, eluting with0-100% Hexane/EtOAc to give title compound. MS (m/z) 537.09 [M+H]+.

Step 2: Preparation of(1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4,4-difluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a solution of(1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-4,7,9-trioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(35 mg, 0.065 mmol) in DCM (2.0 mL) at 0° C., was added deoxofluorsolution in toluene (50%, 0.072 mL, 0.20 mmol). The reaction was stirredat rt overnight. To the reaction mixture was added more deoxofluorsolution in toluene (50%, 0.072 mL, 0.20 mmol) and stirred at rt. Afterone day, to the mixture was added more deoxofluor solution in toluene(50%, 0.072 mL, 0.20 mmol). The reaction mixture was stirred at rt forabout 2 weeks. Quench the reaction by adding sat NaHCO₃, extracted withDCM. The organic phase was separated, dried over MgSO₄, filtered,concentrated down and the residue was purified by silica gelchromatography, eluting with 0-100% hexane/EtOAc to give title compound.MS (m/z) 559.09 [M+H]+.

Step 3: Preparation of(1S,2R,5S)—N-(2,4-difluorobenzyl)-4,4-difluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

The solution of(1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4,4-difluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(13 mg, 0.023 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at rtovernight. The reaction mixture was concentrated down, and the residuewas purified by reverse phase HPLC, eluting with 5-100%acetonitrile/water to give the title compound. MS (m/z) 469.26 [M+H]⁺.1H NMR (400 MHz, Chloroform-d) δ 10.23 (t, J=5.7 Hz, 1H), 8.56 (s, 1H),7.38 (td, J=8.7, 6.4 Hz, 1H), 6.90-6.78 (m, 2H), 5.06 (dp, J=14.1, 7.1Hz, 1H), 4.83-4.56 (m, 4H), 3.37 (tt, J=7.9, 5.1 Hz, 1H), 2.42-2.21 (m,2H), 1.52 (dd, J=7.0, 1.7 Hz, 3H), 1.44 (dd, J=7.3, 2.6 Hz, 3H).

Example 55: Preparation of(1S,2R,5S)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C55)

(1S,2R,5S)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas prepared in a similar method to prepare Example 54, except that(1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas used instead of(1S,2R,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamideand(1S,2R,5S)-8-(benzyloxy)-4-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas the minor product of fluorination reaction. MS (m/z) 467.17 [M+H]⁺.1H NMR (400 MHz, Methanol-d4) δ 10.47 (s, 1H), 8.45 (s, 1H), 6.92 (t,J=8.4 Hz, 2H), 5.53 (d, J=7.7 Hz, 1H), 5.33-5.14 (m, 2H), 4.79 (d,J=14.6 Hz, 1H), 4.69 (t, J=3.5 Hz, 2H), 3.92 (dq, J=6.9, 3.5 Hz, 1H),1.49 (dd, J=7.3, 1.8 Hz, 3H), 1.44 (d, J=6.8 Hz, 3H).

Example 56: Preparation of(1S,2R,4R,5S)-4-(difluoromethyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C56)

Step 1: Preparation of(1S,2R,5S,E)-8-(benzyloxy)-4-(methoxymethylene)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a solution of(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-4,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(120 mg, 0.22 mmol) in methanol (1.5 mL) was added1-diazo-1-dimethoxyphosphoryl-propan-2-one (96 mg, 0.5 mmol) andpotassium tert-butoxide (85 mg, 0.76 mmol) at 0° C. The reaction mixturewas stirred at 0° C. for 45 min. The reaction mixture was diluted withEtOAc, washed with sat. NaHCO₃, extracted with EtOAc, the organic phasewas separated, dried over MgSO₄, filtered, concentrated down andpurified by silica gel column, eluting with 0-100% hexane/EtOAc to givetitle compound. MS (m/z) 583.06 [M+H]+.

Step 2: Preparation of(1S,2R,5S)-8-(benzyloxy)-4-formyl-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,5S,E)-8-(benzyloxy)-4-(methoxymethylene)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(30 mg, 0.051 mmol) was treated with THF (1.5 mL) and 1 N HCl (1.5 mL)in a microwave vial. Then the vial was sealed and heated to 55° C. for 1day. The reaction was quenched with saturated sodium bicarbonatesolution and extracted into EtOAc. The organic phase was washed withbrine, dried over sodium sulfate, filtered and concentrated. The residuewas purified by silica gel chromatography, eluting 0-100% EtOAc/hexane.MS (m/z) 569.07 [M+H]+.

Step 3: Preparation of(1S,2R,4R,5S)-8-(benzyloxy)-4-(difluoromethyl)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a solution of(1S,2R,5S)-8-(benzyloxy)-4-formyl-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(15 mg, 0.026 mmol) in DCM (2.0 mL), was added deoxofluor in toluene(50%, 23 mg, 0.053 mmol) at 0° C. The reaction mixture was stirred at 0°C. for 1 h. The reaction was quenched by adding sat. NaHCO₃ slowly at 0°C., extracted into DCM. The organic phase was separated, dried overMgSO₄, filtered, concentrated down and the residue was purified bysilica gel chromatography, 0-100% EtOAc/hexane to give title compound.MS (m/z) 591.06 [M+H]+.

Step 4: Preparation(1S,2R,4R,5S)-4-(difluoromethyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

The solution of(1S,2R,4R,5S)-8-(benzyloxy)-4-(difluoromethyl)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(5 mg, 0.0085 mmol) in DCM (0.5 mL) and TFA (0.5 mL) was stirred at rtovernight. The reaction mixture was concentrated down, and the residuewas purified by reverse phase HPLC, eluting with 5-100%acetonitrile/water to give title compound. MS (m/z) 501.22 [M+H]⁺. 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 6.98-6.85 (m, 2H), 6.02 (td,J=56.0, 2.8 Hz, 1H), 4.83-4.59 (m, 5H), 3.72 (d, J=7.6 Hz, 1H), 2.47(td, J=8.3, 7.7, 2.8 Hz, 1H), 1.68 (dd, J=6.1, 3.3 Hz, 2H), 1.47 (d,J=6.8 Hz, 3H), 1.42 (d, J=7.2 Hz, 3H).

Example 57: Preparation of(1S,2R,4R,5S)-4-(fluoromethyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C57)

Step 1: Preparation of(1S,2R,4R,5S)-8-(benzyloxy)-4-(hydroxymethyl)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a solution of(1S,2R,5S)-8-(benzyloxy)-4-formyl-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(20 mg, 0.035 mmol) in MeOH (5 mL) at 0° C. was added sodium borohydride(0.65 mg, 0.017 mmol) slowly. The reaction mixture was stirred at 0° C.for 15 min. After the reaction is finished, the reaction was quenched byadding sat. NaHCO₃, extracted with DCM. The organic was separated, driedover MgSO₄, filtered, concentrated down and the residue was used in nextstep without purification. MS (m/z) 571.22 [M+H]+.

Steps 2-3: Preparation of(1S,2R,4R,5S)-4-(fluoromethyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,4R,5S)-4-(fluoromethyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas prepared in the similar method to Example 56, except that(1S,2R,4R,5S)-8-(benzyloxy)-4-(hydroxymethyl)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas used instead of(1S,2R,5S)-8-(benzyloxy)-4-formyl-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 483.29 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H),6.97-6.85 (m, 2H), 4.87-4.72 (m, 2H), 4.69 (d, J=7.3 Hz, 2H), 4.59-4.30(m, 3H), 3.71-3.63 (m, 1H), 2.28 (dddd, J=21.6, 16.5, 10.9, 5.9 Hz, 1H),1.73 (ddd, J=14.5, 10.7, 3.4 Hz, 1H), 1.61 (dd, J=15.5, 3.2 Hz, 1H),1.42 (dd, J=7.0, 4.4 Hz, 6H).

Example 58: Preparation of(1S,2S,4S,5S)—N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C58)

Step 1: Preparation of(1S,2S,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

A solution of(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(0.576 mmol, 300 mg) from Example 30, in i-PrOH (14 mL) was sparged withargon for 10 minutes then treated with phenylsilane (2 equiv, 1.15 mmol,140 uL) and tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III)(0.03 equiv, 0.017 mmol, 10.5 mg) and affixed with a balloon of oxygen.The reaction mixture was stirred at room temperature overnight, at whichpoint additional phenylsilane (1 equiv, 0.576 mmol, 70 uL) andtris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (0.03 equiv,0.017 mmol, 10.5 mg) were added. After stirring for an additional 24hours, the reaction mixture was quenched with 10% sodium thiosulfate andextracted into EtOAc (2×). The combined organic layers were washed withbrine, dried with sodium sulfate, filtered and concentrated. The cruderesidue was purified by silica gel chromatography (0-100% EtOAc inhexanes) to afford(1S,2S,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamideand(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-4,7,9-trioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.Alcohol: MS (m/z) 539.15 [M+H]+. Ketone: MS (m/z) 537.07 [M+H]+.

Step 2: Preparation of(1S,2S,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

A solution of(1S,2S,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(0.033 mmol, 18 mg) in CH2Cl2 (0.3 mL) in a polypropylene tube wastreated with [Bis(2-methoxyethyl)amino]sulfur trifluoride (2.7 M intoluene, 2 equiv, 0.067 mmol, 25 uL) and sealed. After stirring at roomtemperature for one hour, the reaction mixture was carefully quenchedwith saturated sodium bicarbonate then extracted into EtOAc (3×). Thecombined organic layers were washed with brine, dried with sodiumsulfate, filtered and concentrated. The crude residue was carried ondirectly without further purification. MS (m/z) 541.16 [M+H]+.

Step 3: Preparation of(1S,2S,4S,5S)—N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

A solution of crude(1S,2S,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas treated with toluene (0.5 mL) and trifluoroacetic acid (0.5 mL) thenstirred at room temperature for 7 hours. The reaction mixture wasconcentrated and purified by preparative HPLC (10-100% MeCN in water,0.1% TFA) then lyophilized to afford the title compound. MS (m/z) 451.23[M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 7.44 (td, J=8.4,6.3 Hz, 1H), 7.01-6.88 (m, 2H), 5.08 (ddd, J=48.4, 6.7, 5.0 Hz, 1H),4.97-4.89 (m, 1H), 4.89-4.75 (m, 2H), 4.63 (s, 2H), 4.01 (ddt, J=14.6,7.8, 3.9 Hz, 1H), 2.20 (ddd, J=16.1, 6.7, 1.8 Hz, 1H), 1.67 (ddd,J=35.4, 16.1, 11.7 Hz, 1H), 1.42 (dd, J=7.2, 2.3 Hz, 3H), 1.19 (d, J=7.0Hz, 3H).

Example 59: Preparation of(1S,2S,5S)—N-(2,4-difluorobenzyl)-4,4-difluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamideC (59)

Step 1: Preparation of(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4,4-difluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

A solution of(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-4,7,9-trioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(0.065 mmol, 35 mg), prepared according to Example 58, in CH₂Cl₂ (0.65mL) in a polypropylene tube was treated with[Bis(2-methoxyethyl)amino]sulfur trifluoride (2.7 M in toluene, 2 equiv,0.13 mmol, 50 uL) and sealed. After stirring at room temperatureovernight, an additional portion [Bis(2-methoxyethyl)amino]sulfurtrifluoride (2.7 M in toluene, 2 equiv, 0.13 mmol, 50 uL) was added.After an additional 3 hours, the reaction mixture was carefully quenchedwith saturated sodium bicarbonate then extracted into EtOAc (3×). Thecombined organic layers were washed with brine, dried with sodiumsulfate, filtered and concentrated. The crude residue was carried ondirectly without further purification. MS (m/z) 559.10 [M+H]+.

Step 2: Preparation of(1S,2S,5S)—N-(2,4-difluorobenzyl)-4,4-difluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

A solution of crude(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4,4-difluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas treated with toluene (1 mL) and trifluoroacetic acid (1 mL) thenstirred at room temperature for 7 hours. The reaction mixture wasconcentrated and purified by preparative HPLC (10-100% MeCN in water,0.1% TFA) then lyophilized to afford the title compound. MS (m/z) 469.23[M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H), 7.50-7.41 (m, 1H),7.03-6.91 (m, 2H), 5.08-4.96 (m, 1H), 4.97-4.79 (m, 2H), 4.65 (s, 2H),4.04-3.92 (m, 1H), 2.41-2.10 (m, 2H), 1.45 (dd, J=7.2, 2.0 Hz, 3H), 1.23(d, J=6.9 Hz, 3H).

Example 60: Preparation of(4R,5S,13S)—N-(2,4-difluorobenzyl)-10-hydroxy-4,13-dimethyl-9,11-dioxo-4,9,11,13-tetrahydro-1H-5,12-methanoimidazo[4,5-g]pyrido[1,2-b][1,2,5]triazonine-8-carboxamide(C60)

Step 1, Preparation of(1S,2R,3R,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

A solution of(1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(0.48 mmol, 250 mg), prepared according to Example 29, in acetone (10mL) and water (1.25 mL) was cooled to 0° C. then treated with a solutionof N-methylmorpholine N-oxide (50 wt % in water, 1.1 equiv, 0.528 mmol,110 uL) and a solution of osmium tetroxide (2.5 wt % in tert-butanol,0.04 equiv, 0.019 mmol, 195 uL). The reaction mixture was allowed toslowly warm to room temperature and stirred for 4 days then quenchedwith 10% aqueous sodium sulfite and extracted into 1/1 EtOAc/n-BuOH(2×). The combined organic layers were washed with saturated aqueoussodium bicarbonate and brine then dried with sodium sulfate, filteredand concentrated. The crude material was purified by silica gelchromatography (0-20% MeOH in DCM). MS (m/z) 555.12 [M+H]+.

Step 2: Preparation of(1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-3,4,7,9-tetraoxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

A solution of(1S,2R,3R,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(0.283 mmol, 157 mg) in CH₂C₂ (3 mL) was treated with Dess-Martinperiodinane (3 equiv, 0.85 mmol, 360 mg). The reaction mixture wasquenched with 10% sodium thiosulfate, extracted into EtOAc, washed withsaturated sodium bicarbonate (3×) and brine, then dried with sodiumsulfate, filtered and concentrated. The crude material was purified bysilica gel chromatography (0-20% MeOH in DCM). MS (m/z) 569.18 [M+H₃O]+.

Step 3: Preparation of(4R,5S,13S)-10-(benzyloxy)-N-(2,4-difluorobenzyl)-4,13-dimethyl-9,11-dioxo-4,9,11,13-tetrahydro-1H-5,12-methanoimidazo[4,5-g]pyrido[1,2-b][1,2,5]triazonine-8-carboxamide

A solution of(1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-3,4,7,9-tetraoxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(0.054 mmol, 30 mg) in EtOH (0.5 mL) was treated with paraformaldehyde(1.5 equiv, 0.082 mmol, 7.4 mg), ammonium acetate (3 equiv, 0.16 mmol,12.6 mg) and acetic acid (0.5 equiv, 0.027 mmol, 1.6 uL) then stirred atroom temperature for 72 hours. The reaction was then quenched withsaturated aqueous sodium bicarbonate and extracted into EtOAc (3×). Thecombined organic layers were dried with sodium sulfate, filtered andconcentrated. The crude residue was carried on to the next step withoutfurther purification. MS (m/z) 561.23 [M+H]+.

Step 4: Preparation of(4R,5S,13S)—N-(2,4-difluorobenzyl)-10-hydroxy-4,13-dimethyl-9,11-dioxo-4,9,11,13-tetrahydro-1H-5,12-methanoimidazo[4,5-g]pyrido[1,2-b][1,2,5]triazonine-8-carboxamide

A solution of crude(4R,5S,13S)-10-(benzyloxy)-N-(2,4-difluorobenzyl)-4,13-dimethyl-9,11-dioxo-4,9,11,13-tetrahydro-1H-5,12-methanoimidazo[4,5-g]pyrido[1,2-b][1,2,5]triazonine-8-carboxamidewas treated with toluene (1 mL) and trifluoroacetic acid (1 mL) thenstirred at room temperature overnight. The reaction mixture wasconcentrated and purified by preparative HPLC (10-100% MeCN in water,0.1% TFA) then lyophilized to afford the title compound. MS (m/z) 471.21[M+H]+. ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.12 (t, J=5.3 Hz, 1H),8.47 (s, 1H), 8.32 (s, 1H), 7.47-7.37 (m, 1H), 7.01-6.90 (m, 2H), 5.86(q, J=7.0 Hz, 1H), 5.06 (d, J=14.9 Hz, 1H), 4.79 (d, J=14.9 Hz, 1H),4.59 (d, J=6.0 Hz, 2H), 4.55-4.45 (m, 1H), 1.65 (d, J=6.8 Hz, 3H), 1.60(d, J=7.2 Hz, 3H).

Example 61: Preparation of(1S,2R,3S,4R,5S)-8-hydroxy-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C61)

(1S,2R,3S,4R,5S)-8-(benzyloxy)-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(20 mg, 0.033 mmol), prepared in a similar manner as Example 32, wasdissolved in CH₃CN (1.2 mL) added MgBr₂ (18.4 mg, 0.1 mmol) and stirredat 50° C. for 2 h. The reaction was concentrated down and purified viapreparative HPLC, eluting 10-100% acetonitrile (0.1% TFA) in water (0.1%TFA) to give to the title compound. MS (m/z): 511.1 [M+H]+. ¹H NMR (400MHz, Acetonitrile-d₃) δ 10.44 (s, 1H), 8.40 (s, 1H), 6.98-6.73 (m, 2H),4.67-4.56 (m, 2H), 4.50 (t, J=14.8 Hz, 2H), 4.21-4.16 (m, 1H), 3.80 (d,J=7.1 Hz, 1H), 3.61 (d, J=3.1 Hz, 1H), 3.46 (d, J=8.8 Hz, 1H), 3.36 (s,3H), 3.09 (s, 3H), 1.37 (t, J=7.6 Hz, 6H).

Example 62: Preparation of(1S,2R,5S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,3,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C62)

Step 1: Preparation of tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)(3-methylbut-3-en-2-yl)carbamate

tert-butyl(S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)carbamate(700 mg, 1.20 mmol), prepared according to Example 29, was dissolved inTHE (6.0 mL). 3-Methylbut-3-en-2-ol (186 mg, 2.16 mmol) and triphenylphosphine (551 mg, 2.10 mmol) were added. Diisopropyl azodicarboxylate(0.423 mL, 2.04 mmol) was added over a few minutes at ambienttemperature. After 1 hour the reaction was concentrated by rotaryevaporation and the residue was purified by flash chromatography(hexanes.EtOAc) yielding tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)(3-methylbut-3-en-2-yl)carbamate.ES/MS: 651.023 (M+H+).

Step 2: Preparation of3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-N5-(2,4-difluorobenzyl)-1-((3-methylbut-3-en-2-yl)amino)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide

tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)(3-methylbut-3-en-2-yl)carbamate(0.780 g, 1.14 mmol) was dissolved in DCM (6.0 mL) and hydrogen chloridein 1,4-dioxane (4.00 mol/L, 1.42 mL, 5.69 mmol) was added. The reactionwas stirred at ambient temperature for 21 hours. The reaction wasconcentrated and purified by flash chromatography (hexanes:EtOAc)yielding3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-N5-(2,4-difluorobenzyl)-1-((3-methylbut-3-en-2-yl)amino)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide.ES/MS: 551.183 (M+H+).

Step 3: Preparation of3-((S)-but-3-en-2-yl)-N-(2,4-difluorobenzyl)-5-hydroxy-1-(3-methylbut-3-en-2-yl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-N5-(2,4-difluorobenzyl)-1-((3-methylbut-3-en-2-yl)amino)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide(0.630 g, 1.14 mmol) was dissolved in 1:1 DCE:ACN (3.0 mL).Paraformaldehyde (309 mg, 3.43 mmol), acetic acid (0.463 mL, 8.01 mmol),and trifluoroacetic acid (0.443 mL, 5.72 mmol) were added to thesolution. The reaction was heated to 90° C. overnight (˜12 hours). Thereaction mixture was cooled to ambient temperature and concentrated mostof the way by rotary evaporation. The resultant residue was quenchedwith sat. aq. NaHCO₃ and extracted with EtOAc (3×10 mL). The organiclayers were combined and washed with brine (1×20 mL) then dried withsodium sulfate before concentration by rotary evaporation. The residuewas purified by flash chromatography (hexanes:EtOAc) yielding3-((S)-but-3-en-2-yl)-N-(2,4-difluorobenzyl)-5-hydroxy-1-(3-methylbut-3-en-2-yl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide.ES/MS: 473.252 (M+H+).

Step 4: Preparation of5-(benzyloxy)-3-((S)-but-3-en-2-yl)-N-(2,4-difluorobenzyl)-1-(3-methylbut-3-en-2-yl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

3-((S)-but-3-en-2-yl)-N-(2,4-difluorobenzyl)-5-hydroxy-1-(3-methylbut-3-en-2-yl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(117 mg, 0.247 mmol) was dissolved in DMF (2.5 mL). Potassium carbonate(0.205 g, 0.00148 mol) was added followed by benzyl bromide (0.106 g,0.617 mmol). The reaction was heated at 90° C. for 4 hours. The mixturewas cooled to ambient temperature and diluted with water (5 mL). Thereaction was extracted with EtOAc (3×5 mL). The organic layers werecombined and washed with brine (2×10 mL), dried with sodium sulfate andconcentrated by rotary evaporation. The residue was purified by flashchromatography (hexanes:EtOAc) yielding5-(benzyloxy)-3-((S)-but-3-en-2-yl)-N-(2,4-difluorobenzyl)-1-(3-methylbut-3-en-2-yl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide.ES/MS: 563.183 (M+H+).

Step 5: Preparation of(1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,3,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

5-(benzyloxy)-3-((S)-but-3-en-2-yl)-N-(2,4-difluorobenzyl)-1-(3-methylbut-3-en-2-yl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(0.117 g, 0.207 mmol) was dissolved in DCE (6 mL) and Hoveyda-GrubbsCatalyst 2nd Generation (51.9 mg, 0.0828 mmol) was added. The mixturewas sparged with Ar three times then heated to 90° C. overnight (˜12 h).The mixture was cooled to ambient temperature and concentrated by rotaryevaporation. Purification by flash chromatography (Hexanes:EtOAc)yielded(1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,3,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.ES/MS: 535.102 (M+H+).

Step 6: Preparation of(1S,2R,5S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,3,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,3,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(3.10 mg, 5.80 μmol) was dissolved in DMF (500 μL) and lithium chloride(7.00 mg, 165 μmol) was added. The reaction was heated overnight at 90°C. The mixture was cooled to ambient temperature, filtered and purifiedby reverse phase HPLC (water:ACN with 0.1% TFA) to yield(1S,2R,5S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,3,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.ES/MS: 445.213 (M+H+). 1H NMR (400 MHz, Acetonitrile-d3) δ 10.17 (s,1H), 8.34 (s, 1H), 7.41 (q, J=9.0, 8.3 Hz, 1H), 7.09-6.80 (m, 2H), 5.51(d, J=2.3 Hz, 1H), 5.15 (d, J=7.1 Hz, 1H), 5.07 (d, J=14.5 Hz, 1H),4.72-4.40 (m, 3H), 3.83 (d, J=6.9 Hz, 1H), 1.86-1.68 (m, 3H), 1.28 (dd,J=15.0, 7.0 Hz, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ−114.02 (p,J=7.8, 7.4 Hz), −115.37-−118.64 (m).

Example 63: Preparation of(1S,2R,5S)—N-(3-chloro-2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C63)

Step 1: Preparation of tert-butyl((1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carbonyl)(2,4,6-trifluorobenzyl)carbamate

(1S,2R,5S)-8-(Benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(837 mg, 1.55 mmol) was dissolved in toluene (12 mL) at rt. DMAP (570mg, 4.66 mmol) and (Boc)2O (1.355 g, 6.22 mmol) were added sequentially.The reaction mixture was heated with stirring at 110° C. for 2 h and wasthen concentrated to dryness. Residue was purified with silica gelcolumn with 0-100% EtOAc/Hex to afford product. MS (m/z): 639.2 [M+H]+.

Step 2: Preparation of(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxylicacid

Tert-butyl((1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carbonyl)(2,4,6-trifluorobenzyl)carbamate(635 mg, 0.994 mmol) was dissolved in MeOH (12 mL) and then water (6 mL)was added. Then NaOH (1M, 3.5 mL, 3.4 mmol) was added dropwise. Theresulting reaction mixture was stirred at rt for 17 h. Reaction mixturewas then diluted with water (20 mL) and was acidified to pH=3 with 1NHCl. EtOAc (50 mL) was added for extraction. Organic phase was separatedand washed with brine (50 mL). Organic phase was separated and driedover Na2SO4. Filtration and concentration afforded a crude product whichwas purified by reverse phase preparative HPLC with 0-100% acetonitrilein water with 0.1% TFA to afford the desired product. MS (m/z): 396.1[M+H]+.

Step 3: Preparation of(1S,2R,5S)-8-(Benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,5S)-8-(Benzyloxy)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxylicacid (13 mg, 0.0329 mmol) was dissolved in DMF (1 mL) at rt. DIEA (17mg, 0.132 mmol) was added under argon atmosphere. The resulting reactionmixture was cooled to 0° C. Then HATU (18.8 mg, 0.0493 mmol) was added.The resulting reaction mixture was then warmed up to rt and stirred atrt for 1 h. To this reaction mixture, was added a solution of(3-chloro-2,4-difluorophenyl)methanamine (8.76 mg, 0.0493 mmol) in DMF(0.5 mL). The reaction mixture was then stirred at rt for 17 h. Reactionmixture was diluted with EtOAc (10 mL) and was treated with a mixture ofsaturated aqueous NH4Cl solution (10 mL) and water (10 mL). Organicphase was then washed with water (10 mL) and saturated brine (10 mL)sequentially. Organic phase was then separated and concentrated. Theresidue was purified on silica gel column with 0-100% EtOAc/Hex toafford product. MS (m/z): 555.2 [M+H]+.

Step 4: Preparation of(1S,2R,5S)—N-(3-chloro-2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,5S)-8-(Benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(17 mg, 0.0306 mmol) was dissolved in toluene (2 mL) at rt. TFA (2 mL)was added carefully with stirring. The resulting reaction mixture wasstirred at rt for 17 h. Reaction mixture was then concentrated todryness. The residue was taken up in MeOH and was purified with reversephase prep-HPLC with 0-100% CH₃CN in water with 0.1% TFA to afford thedesired product. Lyophilization afforded product. MS (m/z): 465.2[M+H]+. 1H NMR (400 MHz, CD3CN) δ 10.26 (s, 1H), 8.39 (s, 1H), 7.38 (td,J=8.4, 6.1 Hz, 1H), 7.10 (td, J=8.7, 1.8 Hz, 1H), 5.66 (dt, J=11.4, 2.4Hz, 1H), 5.46-5.31 (m, 2H), 5.02 (d, J=14.4 Hz, 1H), 4.64 (m, 2H), 4.58(d, J=14.4 Hz, 1H), 3.84 (tq, J=6.7, 3.6 Hz, 1H), 1.35 (dd, J=7.1, 2.3Hz, 6H).

Example 64: Preparation of(1S,2R,5R)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C64)

(1S,2R,5R)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas prepared in a similar manner as Example 24, except using(R)-but-3-en-2-amine hydrochloride instead of (S)-but-3-en-2-aminehydrochloride in Step 4. MS (m/z): 449.2 [M+H]+. 1H NMR (400 MHz, CD3CN)δ 10.31 (s, 1H), 8.39 (s, 1H), 6.93-6.81 (m, 2H), 5.80 (ddd, J=11.7,2.7, 1.9 Hz, 1H), 5.45 (ddd, J=11.7, 4.1, 2.4 Hz, 1H), 4.82-4.55 (m,4H), 4.32 (dtt, J=7.4, 5.0, 2.5 Hz, 1H), 4.01 (ddt, J=6.8, 4.5, 2.2 Hz,1H), 1.79 (d, J=7.5 Hz, 3H), 1.40 (d, J=7.0 Hz, 3H).

Example 65: Preparation of(1S,2R,5R)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C65)

(1S,2R,5R)-8-Hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(25 mg, 0.0558 mmol), prepared according to Example 64, was dissolved inMeOH (10 mL). Pd/C (10%) (12 mg) was added. Hydrogenolysis was performedwith H₂ balloon at rt for 7 h. Reaction mixture was filtered throughcelite. Filtrate was collected and concentrated to dryness. The residuewas taken up in MeOH and was purified with reverse phase prep-HPLC with0-100% CH₃CN in water with 0.1% TFA to afford the desired product.Lyophilization afford product. MS (m/z): 451.2 [M+H]. 1H NMR (400 MHz,CD3CN) δ 10.30 (s, 1H), 8.38 (s, 1H), 6.87 (t, J=8.5 Hz, 2H), 4.75-4.51(m, 4H), 3.60-3.42 (m, 1H), 3.00 (dq, J=12.2, 6.4 Hz, 1H), 1.59-1.76 (m,4H), 1.73 (d, J=7.0 Hz, 3H), 1.30 (d, J=6.5 Hz, 3H).

Example 66: Preparation of(1R,2S,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C66)

(1R,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(16 mg, 0.0297 mmol), prepared according to Example 24, was dissolved inMeOH (10 mL). Pd—C (10%) (12 mg) was added. Hydrogenolysis was performedwith H₂ balloon at rt for 7 h. Reaction mixture was filtered throughcelite. Filtrate was collected and concentrated to dryness. The residuewas taken up in MeOH and was purified with reverse phase prep-HPLC with0-100% CH₃CN in water with 0.1% TFA to afford the desired product.Lyophilization afford product. MS (m/z): 451.2 [M+H]. 1H NMR (400 MHz,CD₃CN) δ 10.30 (s, 1H), 8.38 (s, 1H), 6.87 (t, J=8.5 Hz, 2H), 4.75-4.51(m, 4H), 3.60-3.42 (m, 1H), 3.00 (dq, J=12.2, 6.4 Hz, 1H), 1.59-1.76 (m,4H), 1.73 (d, J=7.0 Hz, 3H), 1.30 (d, J=6.5 Hz, 3H).

Example 67: Preparation of(1S,2R,5R)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C67)

Step 1: Preparation of(1R,2S,5R)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(A1),(1R,2R,5R)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(B1), and(1S,2R,5R)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C1)

5-(benzyloxy)-3-((R)-but-3-en-2-yl)-1-(but-3-en-2-yl)-N-(2,4-difluorobenzyl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(390 mg, 0.711 mmol), prepared in a similar manner as Example 29 exceptusing (R)-but-3-en-2-amine instead of (S)-but-3-en-2-amine, wasdissolved in dichloromethane (60 mL) at room temperature. Argon wasbubbled through the reaction solution for 20 min. HG-M720 catalyst (44.5mg, 0.071 mmol) was then added with stirring. The purging with argon wascontinued for 10 min. The reaction mixture was then heated with refluxcondenser under argon atmosphere for 24 hrs. The resulting reactionmixture was then concentrated to dryness. The crude material waspurified on silica gel column with 0-100% EtOAc/Hex to afford threediastereomers. MS (m/z): 521.1 [M+H]+.

Step 2: Preparation of(1S,2R,5R)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,5R)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(10 mg, 0.019 mmol) was dissolved in EtOH (3 mL) and added 10% Pd—C (4mg, 0.0038 mmol). Hydrogenolysis was performed with H₂ balloon at rt for7 h. Reaction mixture was filtered through pad of Celite. Filtrate wascollected and concentrated to dryness. The residue was taken up in MeOHand was purified with reverse phase prep-HPLC with 50-100% CH₃CN inwater with 0.1% TFA to afford the desired product. MS (m/z): 433.2[M+H]+. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.33 (d, J=30.5 Hz, 1H),8.41 (d, J=19.1 Hz, 1H), 7.43 (td, J=9.2, 8.8, 6.5 Hz, 1H), 7.06-6.85(m, 2H), 4.71 (d, J=14.9 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 4.56 (s, 1H),3.51 (ddt, J=11.2, 7.1, 3.5 Hz, 1H), 3.31-3.01 (m, 1H), 2.07-1.99 (m,1H), 1.93-1.66 (m, 6H), 1.30 (p, J=6.6 Hz, 3H).

Example 68: Preparation of(1R,2R,5R)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C68)

(1R,2R,5R)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(21 mg, 0.04 mmol), prepared according to Example 67, was dissolved inCH₃CN (2 mL), added MgBr₂ (22.3 mg, 0.22 mmol) and stirred at 50° C. for2 h. Reaction mixture was quenched with water (1 mL) to form clearsolution, filtered and the residue was taken up in MeOH and was purifiedwith reverse phase prep-HPLC with 50-100% CH₃CN in water to afford thedesired product. MS (m/z): 431.2 [M+H]+. 1H NMR (400 MHz,Acetonitrile-d3) δ 10.28 (s, 1H), 8.45 (s, 1H), 7.44 (q, J=9.1, 8.4 Hz,1H), 6.98 (tt, J=10.9, 3.1 Hz, 2H), 5.69-5.54 (m, 1H), 5.47-5.26 (m,2H), 4.94 (d, J=14.3 Hz, 1H), 4.73 (d, J=14.4 Hz, 1H), 4.61 (d, J=5.7Hz, 3H), 1.36 (d, J=7.2 Hz, 3H), 1.03 (d, J=7.3 Hz, 3H).

Example 69: Preparation of(1S,2R,5R)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C69)

(1S,2R,5R)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(8 mg, 0.015 mmol), prepared according to Example 67, was dissolved inCH₃CN (2 mL), added MgBr2 (6.2 mg, 0.034 mmol) and stirred at 50° C. for2 h. Reaction mixture was quenched with water (1 mL) to form clearsolution, filtered and the residue was taken up in MeOH and was purifiedwith reverse phase prep-HPLC with 50-100% CH₃CN in water to afford thedesired product. MS (m/z): 431.1 [M+H]+. 1H NMR (400 MHz,Acetonitrile-d3) δ 10.31 (s, 1H), 8.44 (d, J=9.2 Hz, 1H), 7.44 (h, J=6.6Hz, 1H), 6.98 (dt, J=13.7, 4.9 Hz, 2H), 5.89-5.72 (m, 1H), 5.55-5.33 (m,1H), 4.83-4.67 (m, 2H), 4.66-4.52 (m, 2H), 4.33 (ddd, J=8.8, 5.6, 3.2Hz, 1H), 4.23-3.90 (m, 1H), 1.80 (d, J=7.5 Hz, 3H), 1.41 (d, J=7.0 Hz,3H).

Example 70: Preparation of(1S,2R)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C70)

(1S,2R)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas prepared in a similar manner as Example 24, except using allylammonium chloride instead of (S)-but-3-en-2-amine hydrochloride in Step4. ES/MS (m/z): 435.199 [M+H]+, 1H NMR (400 MHz, Acetonitrile-d3) δ10.19 (s, 1H), 8.37 (s, 1H), 6.85 (t, J=8.6 Hz, 2H), 5.74 (dq, J=11.7,2.8 Hz, 1H), 5.43 (ddt, J=11.8, 3.6, 2.2 Hz, 1H), 4.95 (dq, J=18.4, 2.9Hz, 1H), 4.84 (d, J=14.4 Hz, 1H), 4.70 (d, J=14.3 Hz, 1H), 4.64-4.57 (m,2H), 3.92-3.74 (m, 2H), 1.36 (d, J=6.8 Hz, 3H).

Example 71: Preparation of(1S,2R)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C71)

To a vial were added(1S,13R)-6-hydroxy-13-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide(37.6 mg, 0.086 mmol, 1.0 eq), prepared according to Example 70,platinum (IV) oxide (1 mg, 4.3 umol, 5 mol %) and ethyl acetate (1.5mL). The vial was then fitted with a hydrogen balloon and the hydrogenwas bubbled through the reaction mixture for 5 minutes. The reaction wasleft under a hydrogen atmosphere for 39 hours whereupon the greysuspension was filtered and the volatiles were removed in vacuo and theresultant residue was purified via preparative HPLC (0-100% CH₃CN/H₂Owith 0.1% TFA modifier) affording(1S,2R)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.ES/MS (m/z): 437.168 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 10.20 (s,1H), 8.54 (s, 1H), 6.66 (t, J=8.1 Hz, 2H), 4.76-4.58 (m, 3H), 4.49-4.36(m, 2H), 3.26-3.16 (m, 1H), 3.05 (dt, J=13.4, 6.5 Hz, 1H), 1.98 (q,J=5.5 Hz, 2H), 1.74 (q, J=5.0 Hz, 2H), 1.35 (d, J=6.8 Hz, 3H).

Example 72: Preparation of(1S,2R,5S)-2-ethyl-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C72)

Preparation of5-(benzyloxy)-3-((S)-but-3-en-2-yl)-4,6-dioxo-1-(pent-1-en-3-yl)-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

To a solution of(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(500 mg, 0.976 mmol), prepared according to Example 46, in THF, wasadded 1-ethylallyl acetate (625 mg, 4.88 mmol),1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 g, 9.76 mmol) andtetrakis(triphenylphosphine)palladium(0) (225 mg, 0.195 mmol). Thereaction mixture was heated at 65° C. After the reaction was finished,the reaction mixture was concentrated down and the residue was purifiedthrough silica gel chromatography, eluting with 0-100% hexane/EtOAc. MS(m/z) 581.19 [M+H]+.

Preparation of(1S,2R,5S)-8-(benzyloxy)-2-ethyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(A) and(1S,2S,5S)-8-(benzyloxy)-2-ethyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(B)

The solution of(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(60 mg, 0.103 mmol) in DCE (8 mL), was degassing with Ar for 5 min. Tothe mixture was added cat. Hoverda-Grubbs II catalyst M720 (6.5 mg,0.013 mmol) and the mixture was sparged with Ar for 10 min. Then thereaction mixture was stirred at 80° C. overnight. The reaction mixturewas concentrated down, the residue was purified by silica gelchromatography, eluting with 0-100% hexane/EtOAc to give(1S,2R,5S)-8-(benzyloxy)-2-ethyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(A) as the major product and(1S,2S,5S)-8-(benzyloxy)-2-ethyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(B) as the minor product.

(1S,2R,5S)-8-(benzyloxy)-2-ethyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(A): MS (m/z) 553.06 [M+H]+.

(1S,2S,5S)-8-(benzyloxy)-2-ethyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(B): MS (m/z) 553.05 [M+H]⁺.

Preparation of(1S,2R,5S)-2-ethyl-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

The solution of(1S,2R,5S)-8-(benzyloxy)-2-ethyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(15 mg, 0.0258 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at rtovernight. The mixture was then concentrated down and purified byreverse phase HPLC, 5-100% acetonitrile in water to give the titleproduct. MS (m/z) 462.21 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.43(s, 1H), 7.01-6.84 (m, 2H), 5.77 (dt, J=11.6, 2.4 Hz, 1H), 5.58-5.46 (m,1H), 5.42 (dt, J=7.5, 2.8 Hz, 1H), 5.08 (d, J=14.4 Hz, 1H), 4.75-4.56(m, 3H), 3.76 (dp, J=6.7, 3.4 Hz, 1H), 1.88-1.59 (m, 2H), 1.39 (d, J=7.3Hz, 3H), 1.08 (t, J=7.3 Hz, 3H).

Example 73: Preparation of(1S,2R,5S)-2-ethyl-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C73)

To a solution of(1S,2R,5S)-2-ethyl-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(5 mg, 0.011 mmol), prepared according to Example 72, in EtOH (2 ml) wasadded PtO₂ (1 mg). The reaction mixture was stirred at rt under H₂balloon for 2 h. The reaction mixture was filtered through celite,concentrated down. The residue was purified by reverse phase HPLC,5-100% ACN/H2O, containing 0.1% TFA to give title compound. MS (m/z)465.24 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 6.97-6.87(m, 2H), 4.80-4.52 (m, 5H), 3.24 (t, J=7.1 Hz, 1H), 2.04 (dt, J=14.3,6.9 Hz, 1H), 1.97-1.66 (m, 3H), 1.63-1.43 (m, 2H), 1.31 (d, J=6.7 Hz,3H), 1.19 (t, J=7.3 Hz, 3H).

Example 74: Preparation of(1S,2R,5S)-8-hydroxy-2-isopropyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C74)

Preparation of(1S,2R,5S)-8-(benzyloxy)-2-isopropyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,5S)-8-(benzyloxy)-2-isopropyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas prepared in a similar as(1S,2R,5S)-8-(benzyloxy)-2-ethyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidein Example 72, except that methyl (4-methylpent-1-en-3-yl) carbonate wasused instead of pent-1-en-3-yl acetate. MS (m/z) 567.08 [M+H]+.

Preparation of(1S,2R,5S)-8-hydroxy-2-isopropyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

The reaction mixture of(1S,2R,5S)-8-(benzyloxy)-2-isopropyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(10 mg, 0.017 mmol) and lithium chloride (7.5 mg, 0.17 mmol) in DMF (1mL) was heated at 100° C. overnight. The reaction mixture was filtered,the solution was purified by reverse phase HPLC, eluting with 5-100%acetonitrile/water to give title compound. MS (m/z) 477.21 [M+H]⁺. 1HNMR (400 MHz, Methanol-d4) δ 8.42 (s, 1H), 6.95-6.86 (m, 2H), 5.83 (dt,J=11.7, 2.4 Hz, 1H), 5.56 (dt, J=11.8, 3.1 Hz, 1H), 5.42 (dtd, J=9.9,7.0, 4.1 Hz, 1H), 5.05 (d, J=14.4 Hz, 1H), 4.75-4.62 (m, 3H), 3.67 (p,J=3.3 Hz, 1H), 2.00 (dtq, J=10.4, 7.0, 3.9 Hz, 1H), 1.39 (d, J=7.3 Hz,3H), 1.17 (d, J=6.7 Hz, 3H), 0.92 (d, J=7.0 Hz, 3H).

Example 75: Preparation of(1S,2S,5S)-8-hydroxy-2-isopropyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C75)

(1S,2S,5S)-8-hydroxy-2-isopropyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas synthesized in similar method as Example 73, except that(1S,2R,5S)-8-hydroxy-2-isopropyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas used instead of(1S,2R,5S)-2-ethyl-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 479.21 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H),6.91 (t, J=8.4 Hz, 2H), 4.82-4.53 (m, 5H), 2.89 (d, J=10.0 Hz, 1H),2.11-1.98 (m, 2H), 1.94 (dp, J=16.1, 4.4, 3.9 Hz, 1H), 1.73 (dt, J=14.7,10.2 Hz, 1H), 1.44 (ddd, J=14.8, 11.0, 3.1 Hz, 1H), 1.30 (dd, J=10.4,6.6 Hz, 6H), 0.97 (s, 3H).

Example 76: Preparation of(1S,2S,5S)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C76)

Step 1: Synthesis of3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid

Methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(5.9 g, 10.5 mmol) was dissolved in 100 mL MeOH and 20 mL water, lithiumhydroxide (1.26 g. 52.5 mmol) was added at room temperature, then heatto 60° C. overnight, then 70° C. for 8 hours. The reaction was cooled to0° C., 2 N HCl was added to adjust pH to 3. The reaction crude wasconcentrated down. 100 mL EtOAc was added. The precipitate was filteredand washed with water (30 mL 2×). The solid was dried on vacuum to give4.82 g3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid.

Step 2: Synthesis tert-butyl(S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)carbamate

3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid (5.2 g, 9.5 mmol) and (2S)-but-3-en-2-amine HCl salt (1.23 g, 11.4mmol) were dissolved in anhydrous DMF (500 mL), cooled to ° C. HATU (4.3g, 11.4 mmol) and 1-hydroxy-7-azabenzotriazole (388 mg, 2.85 mmol) wereadded, followed by DIEA (4.96 mL, 28.5 mmol). The reaction was kept at0° C. 10 minutes, the reaction was complete. Poured the reaction mixtureinto ice-water, extract with EtOAc (400 mL 2×). The organic layers wereconcentrated down and purified by silica column, elute with EtOAc/hexane(20-70%) to give tert-butyl(S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)carbamate.MS (m/z) 601.2 [M+H]⁺.

Step 3: Synthesis of tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)((S)-1-hydroxybut-3-en-2-yl)carbamate

Tert-butyl(S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)carbamate(5.09 g, 8.48 mmol) was dissolved in 500 mL anhydrous MeCN,Tetrabutylammonium bromide (5.46 g. 17 mmol) was added, followed by(R,R)-DACH naphthyl Trost ligand (804 mg, 1.02 mmol) andtris(dibenzylideneacetone) dipalladium (439 mg, 0.424 mmol). Purge Arfor 10 minutes, then butadiene monoxide (1.71 mL, 21.2 mmol) was addeddropwise to the reaction. The reaction was stirred at room temperaturefor 3 hours. The reaction crude was concentrated down and purified bysilica column, elute with EtOAc/hexane (30-70%) to give tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)((S)-1-hydroxybut-3-en-2-yl)carbamate.MS (m/z) 671.3 [M+H]⁺.

Step 4: Synthesis of(S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)(tert-butoxycarbonyl)amino)but-3-en-1-ylacetate

Tert-butyl(3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)((S)-1-hydroxybut-3-en-2-yl)carbamate(1.54 g, 2.29 mmol) was dissolved in pyridine (30 mL) and aceticanhydride (3.25 mL, 34.4 mmol) and 1-hydroxy-7-azabenzotriazole (388 mg,2.85 mmol) were added, followed by DMAP (560 mg, 4.59 mmol). Thereaction was heated at 50° C. for 4 days. The reaction crude wasconcentrated down and purified by silica column, elute with EtOAc/hexane(40-70%) to give(S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)(tert-butoxycarbonyl)amino)but-3-en-1-ylacetate. MS (m/z) 713.4 [M+H]⁺.

Step 5: Synthesis of(S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)amino)but-3-en-1-ylacetate

(S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)(tert-butoxycarbonyl)amino)but-3-en-1-ylacetate (1.13 g, 2.29 mmol) was dissolved in dichloromethane (3 mL), 4NHCl in dioxane (4 mL) was added at room temperature. The reaction wasstirred at room temperature for one hour. Reaction was complete. Thecrude reaction was concentrated down and purified by silica column,elute with EtOAc/hexane (40-80%) to give(S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)amino)but-3-en-1-ylacetate. MS (m/z) 613.3 [M+H]⁺.

Step 6: Synthesis of(S)-2-(3-((S)-but-3-en-2-yl)-5-hydroxy-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazin-1-yl)but-3-en-1-ylacetate

(S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)amino)but-3-en-1-ylacetate (405 mg, 0.66 mmol) was dissolved in 1,2-dichloroethane (17 mL)and acetonitrile (17 mL), paraformaldehyde (60 mg, 1.98 mmol) was added.Then acetic acid (0.265 mL, 4.63 mmol) and TFA (0.253 mL, 3.31 mmol)were added to the reaction at the same time. The reaction was heated at90° C. for 20 hours. The crude reaction was concentrated down andpurified by silica column, elute with EtOAc/hexane (40-100%) to give(S)-2-(3-((S)-but-3-en-2-yl)-5-hydroxy-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazin-1-yl)but-3-en-1-ylacetate. MS (m/z) 535.2 [M+H]⁺.

Step 7: Synthesis of(S)-2-(5-(benzyloxy)-3-((S)-but-3-en-2-yl)-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazin-1-yl)but-3-en-1-ylacetate

(S)-2-(3-((S)-but-3-en-2-yl)-5-hydroxy-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazin-1-yl)but-3-en-1-ylacetate (163 mg, 0.3 mmol) was dissolved in DMF (3 mL), K₂CO₃ (208 mg,1.5 mmol) was added, followed by bromomethylbenzene (0.072 mL, 0.6mmol). The reaction was stirred at room temperature overnight. The crudereaction was extracted using EtOAc and sat. NaHCO₃ solution. The organiclayers were concentrated down and purified by silica column, elute withEtOAc/hexane (40-100%) to(S)-2-(5-(benzyloxy)-3-((S)-but-3-en-2-yl)-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazin-1-yl)but-3-en-1-ylacetate. MS (m/z) 625.3 [M+H]⁺.

Step 8: Synthesis of((S,2S,5S)-8-(benzyloxy)-5-methyl-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate

(S)-2-(5-(benzyloxy)-3-((S)-but-3-en-2-yl)-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazin-1-yl)but-3-en-1-ylacetate (210 mg, 0.336 mmol) was dissolved in 1,2-dichloroethane (17mL), Hoveyda-Grubbs Catalyst 2nd Generation (42 mg, 0.067 mmol) wasadded. The reaction was heated at 80° C. for 6 hours. The crude reactionwas concentrated down and purified by silica column, elute withEtOAc/hexane (40-100%) to give((1S,2S,5S)-8-(benzyloxy)-5-methyl-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate. MS (m/z) 597.3 [M+H]⁺.

Step 9: Synthesis of(1S,2S,5S)-8-(benzyloxy)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

((1S,2S,5S)-8-(benzyloxy)-5-methyl-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate (135 mg, 0.226 mmol) was dissolved in MeOH (3 mL), K₂CO₃ (93.8mg, 0.679 mmol) was added. The reaction was stirred at room temperaturefor 15 minutes. EtOAc was added to the crude reaction. Transfer to aseparate funnel, water was added to wash the organic layer twice. Theorganic layer was concentrated down and purified by silica column, elutewith EtOAc/hexane (60-100%) to give(1S,2S,5S)-8-(benzyloxy)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 555.3 [M+H]⁺.

Step 10: Synthesis of(1S,2S,5S)-8-(benzyloxy)-2-(fluoromethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2S,5S)-8-(benzyloxy)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(24 mg, 0.05 mmol) was dissolved in DCM (1.5 mL), cooled to ice bath.Deoxofluor (50% in toluene, 2.7M, 0.39 mL) was added. The reaction wasstirred at 0° C., then warm up to room temperature for 2 hours. Sat.NaHCO₃ solution was added to quench the reaction. Extract using DCM. Theorganic layer was concentrated down and purified via preparative HPLC,eluting 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) to give(1S,2S,5S)-8-(benzyloxy)-2-(fluoromethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 557.2 [M+H]⁺.

Step 11: Synthesis of(1S,2S,5S)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2S,5S)-8-(benzyloxy)-2-(fluoromethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(15 mg, 0.027 mmol) was dissolved in toluene (0.5 mL), TFA (0.5 mL) wasadded. The reaction was stirred at room temperature for 4 hours. Thereaction was concentrated down and purified via preparative HPLC,eluting 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) to give(1S,2S,5S)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 467.2 [M+H]⁺. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 10.21 (s,1H), 8.46 (d, J=1.1 Hz, 1H), 6.87 (t, J=8.5 Hz, 2H), 5.82 (dt, J=11.7,2.8 Hz, 1H), 5.39 (ddt, J=14.7, 12.0, 3.4 Hz, 2H), 4.95 (d, J=14.5 Hz,1H), 4.70-4.59 (m, 4H), 4.54-4.49 (m, 1H), 4.09 (ddd, J=18.4, 5.9, 3.0Hz, 1H), 1.35 (d, J=7.3 Hz, 3H).

Example 77: Preparation of(1S,2S,5S)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C77)

(1S,2S,5S)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(6 mg, 0.013 mmol), prepared according to Example 76, was dissolved inEtOH (5 mL) and EtOAc (5 mL). 10% Pd/C (3 mg) was added and a hydrogenballoon was applied. The reaction was stirred at room temperature for 2hours. The reaction was filtered through celite, the filtrate wasconcentrated down and purified via preparative HPLC, eluting 10-60%acetonitrile (0.1% TFA) in water (0.1% TFA) to give(1S,2S,5S)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 469.2 [M+H]⁺. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.31 (s,1H), 8.40 (s, 1H), 7.01-6.80 (m, 2H), 4.77-4.68 (m, 1H), 4.65-4.56 (m,4H), 4.47 (dd, J=9.9, 5.4 Hz, 1H), 3.67-3.45 (m, 2H), 2.06 (dt, J=13.2,7.0 Hz, 1H), 1.84 (ddd, J=15.5, 7.9, 3.9 Hz, 1H), 1.75-1.60 (m, 2H),1.26 (d, J=6.7 Hz, 3H).

Example 78: Preparation of(1S,2S,5S)-2-(difluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C78)

Step 1: Synthesis of((1S,2S,5S)-8-hydroxy-5-methyl-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate

((1S,2S,5S)-8-(benzyloxy)-5-methyl-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate (48 mg, 0.08 mmol) was dissolved in EtOH (5 mL) and EtOAc (5mL), 10% Pd/C (16 mg) was added, hydrogen balloon was applied. Thereaction was stirred at room temperature for 2 hours. The reaction wasfiltered through celite, the filtrate was concentrated down to give((1S,2S,5S)-8-hydroxy-5-methyl-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate which was used directly in next step. MS (m/z) 509.2 [M+H]⁺.

Step 2: Synthesis of((S,2S,5S)-8-(benzyloxy)-5-methyl-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate

The crude of((1S,2S,5S)-8-hydroxy-5-methyl-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate was dissolved in DMF (3 mL), K₂CO₃ (22 mg, 0.16 mmol) was added,followed by BnBr (0.014 mL, 0.12 mmol). The reaction was stirred at roomtemperature for 2 hours. The reaction was extracted using EtOAc/sat.NaHCO₃, the organic layer was concentrated down, purified by silicacolumn, elute with EtOAc/hexane (60-100%) to give((1S,2S,5S)-8-(benzyloxy)-5-methyl-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate. MS (m/z) 599.3 [M+H]⁺.

Step 3: Synthesis of(1S,2S,5S)-8-(benzyloxy)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

((1S,2S,5S)-8-(benzyloxy)-5-methyl-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate (33 mg, 0.06 mmol) dissolved was in MeOH (1 mL), K2CO3 (24 mg,0.18 mmol) was added. The reaction was stirred at room temperature for15 minutes. EtOAc was added to the reaction crude. Transfer to aseparate funnel, water was added to wash the organic layer twice. Theorganic layer was concentrated down and purified by silica column, elutewith EtOAc/hexane (60-100%) to give(1S,2S,5S)-8-(benzyloxy)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 557.3 [M+H]⁺.

Step 4: Synthesis of(1S,2S,5S)-8-(benzyloxy)-2-formyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2S,5S)-8-(benzyloxy)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(22 mg, 0.039 mmol) was dissolved in DCM (2 mL), Dess-Martin Periodinane(50 mg, 0.12 mmol) was added. The reaction was stirred at roomtemperature, later another 50 mg Dess-Martin Periodinane was added. Thereaction was complete after 4 hours. 10% Na₂S₂O₃ solution was added toquench. The crude was extracted using DCM. The organic layer wasconcentrated down and used in next step directly. MS (m/z) 555.3 [M+H]⁺.

Step 5: Synthesis of(1S,2S,5S)-8-(benzyloxy)-2-(difluoromethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

The crude(1S,2S,5S)-8-(benzyloxy)-2-formyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas dissolved in DCM (1.5 mL), Deoxofluor (50% in toluene, 2.7M, 0.043mL) was added. The reaction was stirred at room temperature, and another0.043 mL of deoxofluor (50% in toluene, 2.7M) was added. The reactionwas stirred at room temperature overnight. Sat. NaHCO₃ solution wasadded to quench the reaction. Extract using DCM. The organic layer wasconcentrated down and purified via preparative HPLC, eluting 10-60%acetonitrile (0.1% TFA) in water (0.1% TFA) to give(1S,2S,5S)-8-(benzyloxy)-2-(difluoromethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 577.3 [M+H]⁺.

Step 6: Synthesis of(1S,2S,5S)-2-(difluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2S,5S)-8-(benzyloxy)-2-(difluoromethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(15 mg, 0.026 mmol) was dissolved in toluene (0.5 mL), TFA (0.5 mL) wasadded. The reaction was stirred at room temperature for 4 hours. Thereaction was concentrated down and purified via preparative HPLC,eluting 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) to give(1S,2S,5S)-2-(difluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 487.2 [M+H]⁺. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.26 (s,1H), 8.44 (s, 1H), 6.87 (t, J=8.5 Hz, 2H), 6.11 (td, J=55.1, 3.5 Hz,1H), 4.72-4.54 (m, 5H), 3.55 (td, J=14.9, 4.1 Hz, 1H), 2.23-2.01 (m,2H), 1.85 (ddd, J=13.9, 10.5, 7.7 Hz, 1H), 1.79-1.59 (m, 1H), 1.26 (d,J=6.9 Hz, 3H).

Example 79: Preparation of(1S,2S,5S)-8-hydroxy-2-(methoxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C79)

Step 1: Synthesis of(1S,2S,5S)-8-(benzyloxy)-2-(methoxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2S,5S)-8-(benzyloxy)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(46 mg, 0.083 mmol), prepared according to Example 76, was dissolved inanhydrous DMF (2 mL), cooled to 0° C., and NaH (60%, 6 mg, 0.014 mL) wasadded. The reaction was kept at 0° C. for 10 minutes. Diluted Mel (1.2eq) was added. The reaction was kept at 0° C. for 10 minutes, thenwarmed up to room temperature for 30 minutes. A drop of water was addedto quench the reaction. The crude reaction was extracted usingEtOAc/sat. NaHCO₃ solution. The organic layer was concentrated andpurified by silica column, eluting with EtOAc/hexane (60-100%), to give(1S,2S,5S)-8-(benzyloxy)-2-(methoxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 569.3 [M+H]⁺.

Step 2: Synthesis of(1S,2S,5S)-8-hydroxy-2-(methoxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2S,5S)-8-(benzyloxy)-2-(methoxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(2 mg, 0.004 mmol) was dissolved in toluene (0.5 mL), TFA (0.5 mL) wasadded. The reaction was stirred at room temperature for 4 hours. Thereaction was concentrated down and purified via preparative HPLC,eluting 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) to give(1S,2S,5S)-8-hydroxy-2-(methoxymethyl)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 479.2 [M+H]⁺. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.59 (s, 1H),6.84 (s, 1H), 6.70 (s, 1H), 5.77 (d, J=12.5 Hz, 1H), 5.41 (d, J=41.9 Hz,2H), 4.96 (m, 1H), 4.67 (d, J=28.6 Hz, 3H), 3.95 (m, 1H), 3.66-3.53 (m,2H), 3.36 (s, 3H), 1.47-1.15 (m, 3H).

Example 80: Preparation of(1R,2R,5S)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C80)

(1R,2R,5S)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas prepared in a similar manner as(1S,2S,5S)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidein Example 76, except using (S,S)-DACH naphthyl Trost ligand instead of(R,R)-DACH naphthyl Trost ligand in Step 3. MS (m/z) 467.2 [M+H]⁺. 1HNMR (400 MHz, Acetonitrile-d3) δ 10.25 (s, 1H), 8.45 (d, J=5.4 Hz, 1H),6.99-6.80 (m, 2H), 6.03-5.93 (m, 1H), 5.41 (ddd, J=12.0, 3.6, 2.5 Hz,1H), 4.94-4.78 (m, 1H), 4.78-4.57 (m, 5H), 4.37-4.15 (m, 2H), 1.88-1.71(m, 3H).

Example 81: Preparation of(1S,2S,5S)—N-(2,4-difluorobenzyl)-2-(difluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C81)

Step 1: Synthesis of((1S,2S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate

((1S,2S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate (170 mg, 0.294 mmol), prepared in a manner similar to Example76, was dissolved in 5 ml of ethanol and 5 ml of ethyl acetate and wassparged under an argon atmosphere. Platinum(IV) oxide (34 mg, 0.15 mmol)was added and the mixture was sparged under a hydrogen atmosphere (1atm, balloon). The mixture was stirred for 20 minutes. After spargedwith argon, it was filtered through a pad of Celite®, and washed withabsolute ethanol. The filtrate was concentrated to dryness and directlyused for next step. MS (m/z): 581.300 [M+H]⁺.

Step 2: Synthesis of(S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

((1S,2S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate (170 mg, 0.293 mmol) was dissolved in 10 ml of methanol. To itwas added potassium carbonate (80.9 mg, 0.589 mmol). The reactionmixture was stirred at room temperature for 10 minutes, partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith brine, dried over magnesium sulfate and concentrated to dryness.The residue was dried under high vacuum to afford the title product. MS(m/z): 539.300 [M+H]+.

Step 3: Synthesis of(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-formyl-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a solution of(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(68 mg, 0.126 mmol) in dry DCM (7 ml) was added Dess-Martin Periodinane(80.3 mg, 0.189 mmol) and the mixture was stirred for 30 minutes at roomtemperature. DCM was added and the organic phase was washed twice with10% sodium thiosulphate solution and once with brine. The organic phasewas dried, evaporated to dryness, and used directly for next step. MS(m/z): 537.288 [M+H]⁺.

Steps 4-5: Synthesis of(1S,2S,5S)—N-(2,4-difluorobenzyl)-2-(difluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-formyl-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(30 mg, 0.0559 mmol) in DCM (2 mL) was cooled at 0° C. under argon. Toit was added Deoxofluor (50% in toluene, 0.103 ml, 0.280 mmol) underargon. The resulting mixture was stirred at 0° C. for 1 hour. Thereaction mixture was diluted with DCM, cooled in an ice/water bath andquenched by dropwise addition of saturated aqueous NaHCO3. The resultingmixture was stirred for 20 minutes. Added more saturated aqueous NaHCO3until no more bubbling. The organic layer was separated, dried overNa2SO4 and the solvent removed under reduced pressure. The residue waspurified by RP-HPLC eluting with ACN/water (w/ 0.1% TFA) to afford(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(difluoromethyl)-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.The residue was dissolved in 1 ml of toluene and 1 ml of TFA, stirred atroom temperature for one hour. Solvent was removed and the residue waspurified by RP-HPLC eluting with ACN/water (w/ 0.1% TFA) to afford thetitle product. MS (m/z): 469.200 [M+H]⁺. ¹H NMR (400 MHz,Acetonitrile-d3) δ 10.26 (s, 1H), 8.45 (s, 1H), 7.49-7.38 (m, 1H),7.03-6.92 (m, 2H), 6.11 (td, J=55.1, 3.6 Hz, 1H), 4.72-4.57 (m, 5H),3.62-3.49 (m, 1H), 2.18-1.99 (m, 2H), 1.88-1.72 (m, 2H), 1.27 (d, J=6.9Hz, 3H).

Example 82: Preparation of(1S,2S,5S)—N-(2,4-difluorobenzyl)-8-hydroxy-2-(methoxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C82)

Step 1: Synthesis of(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas prepared in a manner similar to Step 2 of Example 81, except using((1S,2S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate instead of((1S,2S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methylacetate. MS (m/z): 537.300[M+H]+.

Step 2: Synthesis of(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(methoxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To glass vial charged with(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(25 mg, 0.0466 mmol) under argon was added DMF (2.5 ml) and cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 2.42 mg, 0.0606 mmol)was added and stirred at 0° C. for 20 minutes. Iodomethane (0.0029 ml,0.0466 mmol) was added and stirred for 20 minutes. The reaction wasquenched with saturated ammonium chloride solution, extracted into ethylacetate. Washed organic phase with water, then brine. Back extracted thecombined aqueous phases with more ethyl acetate. Dried combined organicphases over magnesium sulfate, filtered, concentrated in vacuo. Theresidue was purified by silica gel flash column chromatography to affordthe title product. MS (m/z): 551.300[M+H]+.

Step 3: Synthesis of(1S,2S,5S)—N-(2,4-difluorobenzyl)-8-hydroxy-2-(methoxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(methoxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(12 mg, 0.0218 mmol) was dissolved in 1 ml of toluene and 1 ml of TFA,stirred at room temperature for three hours. Solvent was removed and theresidue was purified by RP-HPLC to afford the title product. MS (m/z)461.200[M+H]+. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.23 (s, 1H), 8.55(s, 1H), 7.54-7.38 (m, 1H), 6.98 (ddt, J=13.0, 8.4, 3.1 Hz, 2H), 5.75(dt, J=11.7, 2.7 Hz, 1H), 5.38 (dt, J=12.1, 2.8 Hz, 2H), 4.95 (d, J=14.4Hz, 1H), 4.65-4.57 (m, 3H), 3.91 (dt, J=7.8, 4.3 Hz, 1H), 3.63-3.48 (m,2H), 3.36 (s, 3H), 1.35 (d, J=7.4 Hz, 3H).

Example 83: Preparation of(1S,2S,5S)—N-(2,4-difluorobenzyl)-8-hydroxy-2-(methoxymethyl)-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C83)

(1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(methoxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(9 mg, 0.0163 mmol), prepared according to Example 82, was dissolved in3 ml of ethanol and 3 ml of ethyl acetate, and was sparged under anargon atmosphere. Palladium on carbon (10 wt %, 2 mg) was added and themixture was sparged under a hydrogen atmosphere (1 atm, balloon). Themixture was stirred vigorously for one hour and then sparged under anargon atmosphere. It was filtered through a pad of Celite® and washedwith absolute ethanol. The filtrate was concentrated to dryness. Theresidue was purified by RP-HPLC to afford the title product. MS (m/z)463.200[M+H]+. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.33 (s, 1H), 8.41(s, 1H), 7.44 (td, J=8.8, 6.7 Hz, 1H), 7.03-6.91 (m, 2H), 4.66 (d,J=14.9 Hz, 1H), 4.64-4.50 (m, 4H), 3.65 (dd, J=9.9, 7.0 Hz, 1H),3.51-3.34 (m, 2H), 3.38 (s, 3H), 2.03 (dd, J=14.7, 7.4 Hz, 1H),1.90-1.64 (m, 2H), 1.56 (ddd, J=15.2, 10.9, 3.3 Hz, 1H), 1.26 (d, J=6.8Hz, 3H).

Examples 84 and 85: Preparation of(1′S,3S,5′S)-8′-hydroxy-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamideand(1′S,3R,5′S)-8′-hydroxy-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(C84 and C85)

Step 1: Preparation of di-tert-butyl1-(3-formyltetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate

A mixture of tetrahydrofuran-3-carbaldehyde (2.04 g, 0.02 mol),di-tert-butylazodicarboxylate (3.13 g, 0.014 mol) and L(−)-Proline(0.626 g, 0.54 mmol) in DCE (50 mL) was stirred at 65° C. for 3 days.The reaction mixture was concentrated down, the residue was purified bysilica gel chromatography, eluting with 0-60% hexane/EtOAc to give titlecompound.

Step 2: Preparation of di-tert-butyl1-(3-vinyltetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate

To a suspension of methyltriphenylphosphonium iodide (4.77 g, 11.8 mmol)in THE (50 mL), was added potassium tert-butoxide (1.32 g, 11.8 mmol) at0° C. The reaction mixture was stirred at 0° C. for 5 min. The to themixture was added a solution of di-tert-butyl1-(3-formyltetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate tert-butylN-(tert-butoxycarbonylamino)-N-(3-formyltetrahydrofuran-3-yl)carbamate(1.3 g, 3.93 mmol) in THE (5 mL) at 0° C. Then the reaction mixture wasstirred at rt for 1 h. The reaction was quenched with aq. NH₄Cl at 0°C., extracted with EtOAc and dried over anhyd. Na₂SO₄. The combinedorganic layer was concentrated under reduced pressure to get the crudeproduct which was then purified by silica column chromatography withhexane/acetate (0-60%) as eluents to give title compound.

Step 3: Preparation of (3-vinyltetrahydrofuran-3-yl)hydrazine

The reaction mixture of di-tert-butyl1-(3-vinyltetrahydrofuran-3-yl)hydrazine-1,2-dicarboxylate (820 mg, 3.59mmol) in DCM (3 mL) and TFA (3 mL) was stirred at rt for 1 h. Thereaction mixture was concentrated down and used in next step withoutpurification.

Step 4: Preparation of methyl3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((3-vinyltetrahydrofuran-3-yl)amino)-1,4-dihydropyridine-2-carboxylate

To a solution of (3-vinyltetrahydrofuran-3-yl)hydrazine (460 mg, 3.59mmol) in MeOH (6 mL) and water (1 mL) was added methyl3-benzyloxy-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyran-2-carboxylate(1.6 g, 3.59 mmol) and sodium bicarbonate (1.64 g, 19.6 mmol). Thereaction mixture was stirred at 60° C. overnight. The reaction mixturewas cooled down and the solvent was removed under vacuum. The residuewas washed with water, extracted with EtOAc, the organic phase wasseparated, dried over MgSO₄, filtered, concentrated down and purified bysilica gel chromatography, eluting with 0-100% hexane/EtOAc to givetitle compound. MS (m/z) 558.04 [M+H]+.

Step 5: Preparation of3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((3-vinyltetrahydrofuran-3-yl)amino)-1,4-dihydropyridine-2-carboxylicacid

The reaction mixture of methyl3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((3-vinyltetrahydrofuran-3-yl)amino)-1,4-dihydropyridine-2-carboxylate(760 mg, 1.36 mmol) and lithium hydroxide monohydrate (286 mg, 6.82mmol) in THF (6 mL), MeOH (6 mL) and water (2 mL) was stirred at 60° C.for 4.5 h. Solvent was removed under vacuum. The residue was washed with1N HCl, extracted with DCM. The organic was dried over MgSO₄, filtered,concentrated down. Material was used in next step without purification.MS (m/z) 544.11 [M+H]+.

Step 6: Preparation of3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1-((3-vinyltetrahydrofuran-3-yl)amino)-1,4-dihydropyridine-2,5-dicarboxamide

To a solution of3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((3-vinyltetrahydrofuran-3-yl)amino)-1,4-dihydropyridine-2-carboxylicacid (530 mg, 0.975 mmol) in DMF (3 mL) was added HATU (1.0 g, 2.53mmol) and DIEA (786 mg, 6.09 mmol) at 0° C. Then reaction mixture wasstirred at rt for 1 h. Then the (S)-but-3-en-2-amine HCl salt (315 mg,2.92 mmol) was added at rt in one portion. Reaction mixture was stirredat rt for 5 hr. The reaction mixture was washed with sat. NH₄C1,extracted with EtOAc. The organic phase was separated, dried over MgSO₄,filtered, concentrated down. The residue was purified by silica gelchromatography, eluting with 0-80% hexane/EtOAc to give title compound.MS (m/z) 597.10 [M+H]⁺.

Step 7: Preparation of3-((S)-but-3-en-2-yl)-5-hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-(3-vinyltetrahydrofuran-3-yl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

To a solution of5-(benzyloxy)-3-((S)-but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-(3-vinyltetrahydrofuran-3-yl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(791 mg, 1.33 mmol) in DCE (10 mL)/ACN (10 mL), was addedparaformaldehyde (139 mg, 4.64 mmol), acetic acid (557 mg, 9.28 mmol)and TFA (756 mg, 6.63 mmol). Then the reaction mixture first stirred atrt and then allowed the temp to raise to 82° C. The reaction mixture wasstirred at 82° C. for one day. Then to the mixture was added moreparaformaldehyde (99 mg, 3.31 mmol), acetic acid (557 mg, 9.28 mmol) andTFA (756 mg, 6.63 mmol). The mixture was heated at 82° C. for one moreday. The reaction was cooled down. The reaction mixture was concentrateddown, and the residue was purified by silica gel chromatography, elutingwith 0-100% hexane/EtOAc to afford the title compound. MS (m/z) 519.22[M+H]+.

Step 8: Preparation of5-(benzyloxy)-3-((S)-but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-(3-vinyltetrahydrofuran-3-yl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

To a solution of3-((S)-but-3-en-2-yl)-5-hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-(3-vinyltetrahydrofuran-3-yl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(690 mg, 1.33 mmol) in DMF (10 mL) was added potassium carbonate (920mg, 6.65 mmol) and benzyl bromide (683 mg, 3.99 mmol). The reactionmixture was stirred at 65° C. for 3 h. The reaction was cooled down. Thereaction mixture was washed with water, extracted with EtOAc. Theorganic phase was dried over MgSO₄, filtered, concentrated down. Theresidue was purified by silica gel chromatography, eluting with 0-100%hexane/EtOAc to give the title compound. MS (m/z) 609.12 [M+H]+.

Step 9: Preparation(1′S,3S,5′S)-8′-(benzyloxy)-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(A) and(1′S,3R,5′S)-8′-(benzyloxy)-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(B)

The solution of5-(benzyloxy)-3-((S)-but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-(3-vinyltetrahydrofuran-3-yl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(370 mg, 0.608 mmol) in DCE (10 mL) was sparged with Argon for 5 min.Then to the mixture was addeddichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](3-phenyl-1H-inden-1-ylidene)(tricyclohexylphosphine)ruthenium(II)(86.5 mg, 0.091 mmol) and the mixture was sparged under Argon for 5 min.The mixture was stirred at 80° C. for one day. To the mixture was addedmoredichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](3-phenyl-1H-inden-1-ylidene)(tricyclohexylphosphine)ruthenium(II)(86.5 mg, 0.091 mmol), sparged with Argon and the reaction mixture wasstirred at 80° C. for one week. The reaction mixture was concentrateddown and purified by silica gel chromatography, eluting with 0-100%hexane/EtOAc. Two desired compounds formed in the reaction. The majorproduct can be isolated pure as single diastereomer through silica gelchromatography using 0-100% hexane/EtOAc. The minor product was isolatedpure as diastereomer through SFC chiral separation.

Major diastereomer: MS (m/z) 581.13 [M+H]+.

Minor diastereomer: MS (m/z) 581.09 [M+H]+.

Step 10: Preparation of(1′S,3S,5′S)-8′-hydroxy-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamideand(1′S,3R,5′S)-8′-hydroxy-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide

To a solution of(1′S,3S,5′S)-8′-(benzyloxy)-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(A) in DMF was added LiCl (10 eq). The reaction mixture was heated at100° C. overnight. The reaction mixture was filtered, and the solutionwas purified by reverse phase HPLC, eluting with 5-100%acetonitrile/water.(1′S,3R,5′S)-8′-hydroxy-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamidewas synthesized in similar method, except that(1′S,3R,5′S)-8′-(benzyloxy)-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(B) was used instead of(1′S,3S,5′S)-8′-(benzyloxy)-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(A).

Major diastereomer: MS (m/z) 491.19 [M+H]⁺. 1H NMR (400 MHz,Methanol-d4) δ 8.53 (s, 1H), 6.92 (t, J=8.4 Hz, 2H), 5.68 (dd, J=12.3,2.7 Hz, 1H), 5.53 (dd, J=12.3, 2.2 Hz, 1H), 5.50-5.38 (m, 1H), 5.19 (d,J=14.5 Hz, 1H), 4.77 (d, J=14.5 Hz, 1H), 4.68 (s, 2H), 4.09 (dd, J=8.7,1.3 Hz, 1H), 3.79 (pd, J=8.9, 6.0 Hz, 2H), 3.67 (d, J=8.7 Hz, 1H), 1.94(ddd, J=14.8, 9.3, 5.8 Hz, 1H), 1.51 (dt, J=14.5, 7.4 Hz, 1H), 1.40 (d,J=7.3 Hz, 3H).

Minor diastereomer: MS (m/z) 491.16 [M+H]⁺. 1H NMR (400 MHz,Methanol-d4) δ 8.52 (s, 1H), 6.91 (t, J=8.4 Hz, 2H), 5.80 (dd, J=12.5,3.7 Hz, 1H), 5.48-5.38 (m, 1H), 5.34 (dd, J=12.5, 1.7 Hz, 1H), 5.13 (s,1H), 4.86 (s, 1H), 4.67 (s, 2H), 4.31-4.21 (m, 1H), 4.11 (td, J=8.9, 2.6Hz, 1H), 3.49 (d, J=11.0 Hz, 1H), 3.32-3.26 (m, 1H), 2.58 (dd, J=13.2,7.0 Hz, 1H), 2.25 (dt, J=13.2, 9.3 Hz, 1H), 1.43 (d, J=7.3 Hz, 3H).

Example 86: Preparation of(1′S,5′S)-8′-hydroxy-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,4′,5,5′,7′,9′-hexahydro-2H,3′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(C86)

To a solution of(1′S,5′S)-8′-(benzyloxy)-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7′,9′-tetrahydro-2H,5′H-spiro[furan-3,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(10 mg, 0.017 mmol), the major diastereomer prepared according to Step 9of Examples 84 and 85, in EtOH (1 mL) was added platinum dioxide (2 mg).The reaction mixture was stirred at rt under H₂ balloon overnight. Thereaction mixture was filtered through celite, the filtrate wasconcentrated down and the residue was purified by reverse phase HPLC,eluting with 5-100% acetonitrile/water to give title compound. MS (m/z)493.17 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 6.97-6.87(m, 2H), 4.81 (d, J=14.9 Hz, 1H), 4.75-4.60 (m, 3H), 4.16 (q, J=7.7 Hz,2H), 3.95 (td, J=8.9, 5.0 Hz, 1H), 3.68 (d, J=9.4 Hz, 1H), 2.18 (dt,J=14.6, 6.5 Hz, 1H), 1.92-1.56 (m, 6H), 1.30 (d, J=6.8 Hz, 3H).

Example 87: Preparation of(1S,5S)-8-hydroxy-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C87)

Synthesis of(1S,5S)-8-hydroxy-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,5S)-8-(benzyloxy)-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(0.005 g, 0.009 mmol, 1 equiv.), prepared according to Example 48, wasdissolved in methanol (1 mL) and platinum(IV) oxide (0.2 mg, 0.001 mmol,0.1 equiv.) was added. The vial was sealed, evacuated then backfilledwith hydrogen gas (repeated 2 times). The reaction mixture was spargedwith hydrogen gas for 5 min and left to stir under 1 atm of hydrogen gasfor 4 h. The reaction mixture was filtered and concentrated to afford acrude residue, which was dissolved in MeCN, filtered, and purified bypreparative HPLC (column, Gemini 10μ C18 110A, AXI/; 250×21.2 mm)eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20minutes. Combined fractions were lyophilized to afford(1S,5S)-8-hydroxy-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z) 465.21 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (t, J=6.0 Hz,1H), 8.28 (s, 1H), 7.21 (t, J=8.7 Hz, 2H), 4.79 (d, J=14.8 Hz, 1H), 4.65(d, J=14.8 Hz, 1H), 4.56 (d, J=5.7 Hz, 2H), 4.53-4.44 (m, 1H), 1.96-1.84(m, 1H), 1.71-1.58 (m, 1H), 1.49 (dd, J=15.4, 6.7 Hz, 1H), 1.32 (s, 3H),1.26-1.22 (m, 1H), 1.20 (d, J=6.8 Hz, 3H), 0.92 (s, 3H). ¹⁹F NMR (376MHz, DMSO-d₆) δ−109.16-−109.37 (m), −112.53 (t, J=7.3 Hz).

Examples 88 and 89: Preparation of(1aS,2R,3S,11S,11aR)-8-hydroxy-2,11-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,7,9,11,11a-hexahydro-1H-3,10-methanocyclopropa[g]pyrido[1,2-b][1,2,5]triazonine-6-carboxamideand(1aS,2R,3R,11S,11aR)-8-hydroxy-2,11-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,7,9,11,11a-hexahydro-1H-3,10-methanocyclopropa[g]pyrido[1,2-b][1,2,5]triazonine-6-carboxamide(C88 and C89)

Step 1: Preparation of(S)-but-3-en-2-yl phenyl((S)-but-3-en-2-yl)phosphoramidate

A suspension of(S)-but-3-en-2-amine hydrochloride (1 equiv, 23.2 mmol,2.5 g) and phenyl phosphorodichloridate (1 equiv, 23.2 mmol, 3.47 mL) in40 mL DCM was cooled to −78° C. under argon, treated dropwise withtriethylamine (2 equiv, 46.5 mmol, 6.5 mL), and allowed to slowly warmto room temperature overnight. The reaction mixture was then cooledagain to −78° C., treated with (S)-but-3-en-2-ol (1.5 equiv, 34.9 mmol,2.5 g) followed by the dropwise addition of NMI (2 equiv, 46.5 mmol, 3.7mL) in 10 mL DCM and allowed to slowly warm to room temperatureovernight. The reaction was quenched with water and extracted into EtOAc(3×). The combined organic layers were dried with sodium sulfate,filtered and concentrated. The crude mixture was purified by silica gelchromatography (0-100% EtOAc in hexanes) to afford the desired productas a ˜1:1 mixture of phosphorous diastereomers. MS (m/z) 281.9 [M+H]+.¹H NMR (400 MHz, Chloroform-d) δ 7.36-7.18 (m, 4H), 7.17-7.09 (m, 1H),5.96-5.74 (m, 2H), 5.37-4.92 (m, 4H), 4.01-3.81 (m, 1H), 2.75-2.60 (m,1H), 1.46 (d, J=6.4 Hz, 1.5H), 1.38 (d, J=6.4 Hz, 1.5H), 1.25 (d, J=6.9Hz, 1.5H), 1.23 (d, J=6.8 Hz, 1.5H). ³¹P NMR (162 MHz, Chloroform-d) δ2.63-1.96 (m).

Step 2: Preparation of(4S,7S)-4,7-dimethyl-2-phenoxy-3,4,7-trihydro-1,3,2-oxazaphosphepine2-oxide

A solution of (S)-but-3-en-2-yl phenyl((S)-but-3-en-2-yl)phosphoramidate (11.7 mmol, 3.29 g) in 1,2-DCE (470mL) was sparged with argon for 20 minutes, treated with Hoveyda-GrubbsCatalyst 2nd Generation (0.05 equiv, 366 mg), sparged for an additional5 minutes then stirred at room temperature. An additional portion ofcatalyst was added in the same manner per above at approximately 24 and48 hours. After 72 hours, the reaction mixture was absorbed onto silicagel and purified by silica gel chromatography (0-100% EtOAc in hexanes).The diastereomers eluted in distinct bands but were combined andconcentrated to afford the desired product as a ˜1:1 mixture ofphosphorous diastereomers. Diastereomer 1 (LCMS Rt=1.14 min): MS (m/z)254.19 [M+H]+. Diastereomer 2 (LCMS Rt=1.20 min): MS (m/z) 254.18[M+H]+. ¹H NMR (400 MHz, Chloroform-d) δ 7.37-7.11 (m, 5H), 5.55-5.35(m, 2.5H), 5.24-5.13 (m, 0.5H), 4.24 (h, J=7.2 Hz, 0.5H), 4.13-4.01 (m,0.5H), 3.30 (dd, J=11.8, 7.0 Hz, 0.5H), 3.11 (t, J=6.7 Hz, 0.5H), 1.45(dt, J=6.9, 1.6 Hz, 3H), 1.33 (dd, J=7.1, 2.2 Hz, 1.5H), 1.25 (dd,J=7.1, 2.4 Hz, 1.5H). ³¹P NMR (162 MHz, Chloroform-d) δ 6.08 (s), 4.93(d, J=8.8 Hz).

Step 3: Preparation of tert-butyl((2S,5S,Z)-5-hydroxyhex-3-en-2-yl)carbamate

A solution of(4S,7S)-4,7-dimethyl-2-phenoxy-3,4,7-trihydro-1,3,2-oxazaphosphepine2-oxide (6.32 mmol, 1.6 g) in 60 mL THE was cooled to −78° C. underargon. A solution of lithium aluminum hydride (2 M THF, 3.75 equiv, 23.7mmol, 11 mL) was added dropwise then the reaction mixture was slowlyallowed to warm to room temperature overnight. The reaction was cooledto 0° C. then carefully quenched with 1 mL water, 1 mL 10% aqueous NaOH,and 1.5 mL water, warmed to room temperature, treated with magnesiumsulfate and filtered across Celite with additional CH₂C2. The filtratewas concentrated to afford (2S,5S,Z)-5-aminohex-3-en-2-ol as a clearoil. ¹H NMR (400 MHz, Chloroform-d) δ 5.48-5.31 (m, 2H), 4.66-4.57 (m,1H), 3.91 (p, J=6.7 Hz, 1H), 1.28 (d, J=6.5 Hz, 3H), 1.22 (d, J=6.5 Hz,3H).

The crude reaction mixture containing (2S,5S,Z)-5-aminohex-3-en-2-ol wasdissolved in 65 mL DCM and cooled to 0° C. under argon then treated withtriethylamine (2 equiv, 12.6 mmol, 1.76 mL) and di-tert-butyldicarbonate (1.5 equiv, 9.48 mmol, 2.07 g) and allowed to slowly warm toroom temperature overnight. The reaction mixture was concentrated thendissolved again in EtOAc and washed with half-saturated aqueous sodiumbicarbonate and brine, dried over sodium sulfate, filtered andconcentrated. The crude residue was purified by silica gelchromatography (0-100% EtOAc in hexanes) to afford the desired productas a white solid. MS (m/z) 215.76 [M+H]+. ¹H NMR (400 MHz, Chloroform-d)δ 5.46 (ddd, J=11.1, 7.3, 1.0 Hz, 1H), 5.20 (t, J=10.3 Hz, 1H),4.83-4.61 (m, 2H), 4.45 (bs, 1H), 1.43 (s, 9H), 1.28 (d, J=6.4 Hz, 3H),1.20 (d, J=6.7 Hz, 3H).

Step 4: Preparation of tert-butyl((S)-1-((R,2S)-2-((S)-1-hydroxyethyl)cyclopropyl)ethyl)carbamate)

A solution of diethylzine (1 M in hexanes, 5 equiv, 9.41 mmol, 9.4 mL)in CH₂Cl₂ (4 mL) was cooled to 0° C. under argon, treated dropwise withtrifluoroacetic acid (4.8 equiv, 9.0 mmol, 690 uL) and stirred for 15minutes. Diiodomethane (5 equiv, 9.41 mmol, 760 uL) was added dropwiseand the reaction mixture was stirred for an additional 20 minutes. Asolution of tert-butyl ((2S,5S,Z)-5-hydroxyhex-3-en-2-yl)carbamate (1equiv, 1.88 mmol, 405 mg) in CH₂Cl₂ (2 mL) was added dropwise and thereaction mixture was allowed to slowly warm to room temperatureovernight then quenched with saturated ammonium chloride and extractedinto EtOAc (3×). The combined organic layers were washed with brine,dried with sodium sulfate, filtered and concentrated. The crude residuewas purified by silica gel chromatography (0-100% EtOAc in hexanes) toafford the title compound. MS (m/z) 229.73 [M+H]+. ¹H NMR (400 MHz,Chloroform-d) δ 4.57 (s, 1H), 3.80-3.66 (m, 1H), 3.50-3.33 (m, 1H), 1.43(s, 9H), 1.30 (d, J=6.2 Hz, 3H), 1.25 (d, J=6.3 Hz, 3H), 0.99-0.79 (m,2H), 0.74 (td, J=8.5, 4.5 Hz, 1H), 0.34 (d, J=5.7 Hz, 1H).

Step 5: Preparation of methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)((R)-1-((1S,2R)-2-((S)-1-((tert-butoxycarbonyl)amino)ethyl)cyclopropyl)ethyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate

A solution of tert-butyl((S)-1-((1R,2S)-2-((S)-1-hydroxyethyl)cyclopropyl)ethyl)carbamate (1.2equiv, 0.427 mmol, 98 mg), methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(1 equiv, 0.356 mmol, 200 mg), prepared according to Example 6, andtriphenylphosphine (1.2 equiv, 0.427 mmol, 106 mg) in THE (3.5 mL) wascooled to 0° C. under argon then treated dropwise with diisopropylazodicarboxylate (1.2 equiv, 0.427 mmol, 85 uL) and allowed to slowlywarm to room temperature overnight. The reaction mixture was thentreated with an additional portion of triphenylphosphine and diisopropylazodicarboxylate at 0° C. and again warmed to room temperature overnightthen concentrated and purified by silica gel chromatography (0-100%EtOAc in hexanes) followed by reversed-phase C18 chromatography (0-100%MeCN in water). The combined clean fractions were concentrated thendissolved again in CH₂C2, dried with sodium sulfate, filtered andconcentrated to afford the title product. MS (m/z) 773.01 [M+H]+.

Step 6: Preparation of3-(benzyloxy)-1-((tert-butoxycarbonyl)((R)-1-((1S,2R)-2-((S)-1-((tert-butoxycarbonyl)amino)ethyl)cyclopropyl)ethyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid

A solution of methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)((R)-1-((1R,2S)-2-((S)-1-((tert-butoxycarbonyl)amino)ethyl)cyclopropyl)ethyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate(0.113 mmol, 87 mg) in 3/2/1 THF/MeOH/water (4 mL) was treated withlithium hydroxide (4 equiv, 0.45 mmol, 19 mg) and stirred at roomtemperature overnight. The reaction mixture was treated with anadditional portion lithium hydroxide and further stirred at roomtemperature, then carefully acidified to pH ˜3 with 1 N HCl andextracted into EtOAc (3×). The combined organic layers were washed withbrine, dried with sodium sulfate, filtered and concentrated to affordthe title compound that was carried forward to Step 7 without furtherpurification. MS (m/z) 759.02 [M+H]+.

Step 7: Preparation of(1aS,2R,1S,1aR)-8-(benzloxy)-2,11-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,3,7,9,10,11,11a-octahydro-1H-cyclopropa[g]pyrido[1,2-b][1,2,5]triazonine-6-carboxamide

The crude reaction mixture from Step 6 containing3-(benzyloxy)-1-((tert-butoxycarbonyl)((R)-1-((1R,2S)-2-((S)-1-((tert-butoxycarbonyl)amino)ethyl)cyclopropyl)ethyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid was dissolved in CH₂Cl₂ (200 uL) and 4N HCl/dioxane (70 uL),stirred at room temperature for 3 hours, then concentrated, redissolvedin CH₂Cl₂ and concentrated again (3×) to afford1-(((R)-1-((1R,2S)-2-((S)-1-aminoethyl)cyclopropyl)ethyl)amino)-3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylicacid. MS (m/z) 559.28 [M+H]+. The crude residue was dissolved in CH₂Cl₂(1 mL), treated with N,N-diisopropylethylamine (5 equiv, 0.079 mmol, 14uL) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU, 1.5 equiv, 0.024 mmol, 9.0 mg) then stirredat room temperature overnight. The reaction mixture was diluted withEtOAc, washed with saturated aqueous sodium bicarbonate then furtherextracted with EtOAc (2×). The combined organic layers were dried withsodium sulfate, filtered and concentrated. The crude residue waspurified by silica gel chromatography (0-100% EtOAc in hexanes) toafford the title compound. MS (m/z) 541.10 [M+H]+.

Step 8: Preparation of(1aS,2R,3S,11S,11aR)-8-(benzyloxy)-2,11-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,7,9,11,1a-hexahydro-JH-3,10-methanocyclopropa[g]pyrido[1,2-b][1,2,5]triazonine-6-carboxamideand (1aS,2R,3R,11S,1aR)-8-(benzyloxy)-2,11-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzl)-1a,2,7,9,11,11a-hexahydro-1H-3,10-methanocyclopropa[g]pyrido[1,2-b][1,2,5]triazonine-6-carboxamide

A solution of (1aS,2R,11S,11aR)-8-(benzyloxy)-2,11-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,3,7,9,10,11,11a-octahydro-1H-cyclopropa[g]pyrido[1,2-b][1,2,5]triazonine-6-carboxamide(0.044 mmol, 23.7 mg) in 1/1 MeCN/1,2-DCE (0.8 mL) was treated withparaformaldehyde (3 equiv, 0.13 mmol, 12 mg), acetic acid (7 equiv, 0.31mmol, 18 uL), and trifluoroacetic acid (5 equiv, 0.22 mmol, 17 uL) thenheated to 85° C. for 90 minutes. The reaction mixture was concentratedthen dissolved again in EtOAc and washed with saturated aqueous sodiumbicarbonate and the aqueous layer was further extracted with EtOAc (2×).The combined organic layers were dried with sodium sulfate, filtered andconcentrated. The crude residue was purified by silica gelchromatography (0-100% EtOAc in hexanes) followed by preparative TLC(EtOAc) to afford the title compound as separated diastereomers. Minordiastereomer (LCMS Rt=1.51 min): MS (m/z) 553.07 [M+H]+. Majordiastereomer (LCMS Rt=1.55 min): MS (m/z) 553.09 [M+H]+.

Step 9: Preparation of(1aS,2R,3S,11S,11aR)-8-hydroxy-2,11-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,7,9,11,11a-hexahydro-1H-3,10-methanocyclopropa[g]pyrido[1,2-b][1,2,5]triazonine-6-carboxamide(C88)

A solution of(1aS,2R,3S,11S,11aR)-8-(benzyloxy)-2,11-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,7,9,11,11a-hexahydro-1H-3,10-methanocyclopropa[g]pyrido[1,2-b][1,2,5]triazonine-6-carboxamide(0.0081 mmol, 4.5 mg), the minor diastereomer from Step 8, in DMF (0.15mL) was treated with lithium chloride (10 equiv, 0.081 mmol, 3.5 mg) andheated to 100° C. for 6 hours. The reaction mixture was cooled to roomtemperature, diluted with MeOH/MeCN/TFA, filtered, purified bypreparative HPLC (10-100% MeCN in water, 0.1% TFA) and lyophilized toafford the title compound. MS (m/z) 463.29 [M+H]+. ¹H NMR (400 MHz,Chloroform-d) δ 10.35 (t, J=4.9 Hz, 1H), 8.48 (s, 1H), 6.73-6.60 (m,2H), 5.13 (q, J=7.1 Hz, 1H), 4.67 (s, 2H), 4.64 (d, J=8.9 Hz, 1H), 4.49(d, J=14.3 Hz, 1H), 4.29 (p, J=6.9 Hz, 1H), 1.50 (d, J=7.1 Hz, 3H),1.23-1.17 (m, 2H), 1.18 (d, J=7.0 Hz, 3H), 1.12 (q, J=8.0 Hz, 1H), 0.17(q, J=6.9 Hz, 1H).

Step 10: Preparation of(1aS,2R,3R,11S,11aR)-8-hydroxy-2,11-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,7,9,11,11a-hexahydro-1H-3,10-methanocyclopropa[g]pyrido[1,2-b][1,2,5]triazonine-6-carboxamide(C89)

A solution of(1aS,2R,3R,11S,11aR)-8-(benzyloxy)-2,11-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,7,9,11,11a-hexahydro-1H-3,10-methanocyclopropa[g]pyrido[1,2-b][1,2,5]triazonine-6-carboxamide(0.01 mmol, 5.5 mg), the major diastereomer from Step 8, in EtOH (0.2mL) was purged with argon then treated with 10% palladium on carbon (2mg), affixed with a hydrogen balloon and purged with hydrogen (3×).After 30 minutes, the reaction mixture was filtered across Celite,concentrated, purified by preparative HPLC (10-100% MeCN in water, 0.1%TFA) and lyophilized to afford the title compound. MS (m/z) 463.21[M+H]+. ¹H NMR (400 MHz, Chloroform-d) δ 10.40 (t, J=5.1 Hz, 1H), 8.62(s, 1H), 6.71-6.62 (m, 2H), 4.77-4.59 (m, 3H), 4.44 (d, J=15.0 Hz, 1H),4.44-4.34 (m, 1H), 3.01 (dq, J=10.0, 6.8 Hz, 1H), 1.94-1.86 (m, 1H),1.85 (d, J=6.7 Hz, 3H), 1.39 (d, J=7.5 Hz, 3H), 1.12 (td, J=8.8, 5.4 Hz,1H), 1.00 (q, J=5.7 Hz, 1H), 0.91 (qd, J=8.7, 5.6 Hz, 1H).

Example 90: Preparation of(1S,2R)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C90)

Step 1: Preparation of(1S,2R)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(A),(1R,2S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(B), and(1S,2S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C)

5-(benzyloxy)-1-(but-3-en-2-yl)-N-(2,4-difluorobenzyl)-3-(2-methylbut-3-en-2-yl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(400 mg, 0.711 mmol), prepared in a manner similar to Example 29 exceptusing 2-methylbut-3-en-2-amine instead of (S)-but-3-en-2-amine, wasdissolved in dichloromethane (60 mL) at room temperature. Argon wasbubbled through the reaction solution for 20 min. HG-M720 catalyst (44.5mg, 0.071 mmol) was then added with stirring. The purging with argon wascontinued for 10 min. The reaction mixture connected with refluxcondenser (Vacuuming, flushing with argon three times) then heated withstirring under argon atmosphere for 24 hrs. The resulting reactionmixture was then concentrated to dryness. The crude material waspurified on silica gel column with 0-100% EtOAc/Hex to afford threediastereomers.(1S,2R)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(A): MS (m/z): 535.1 [M+H]+.(1R,2S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(B): MS (m/z): 535.0 [M+H]+.(1S,2S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C): MS (m/z): 535.1 [M+H]+.

Step 2: Preparation of(1S,2R)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(25 mg, 0.0.56 mmol) was dissolved in CH₃CN (3 mL) added MgBr₂ (38 mg,0.206 mmol) and stirred at 50° C. for 2 h. Reaction mixture was quenchedwith water (1 mL) to form clear solution, filtered and the residue wastaken up in MeOH and was purified with reverse phase prep-HPLC with50-100% CH₃CN in water to afford the desired product. MS (m/z): 445.1[M+H]+. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.39 (s, 1H), 8.41 (s, 1H),7.44 (td, J=9.2, 8.8, 6.5 Hz, 1H), 7.03-6.90 (m, 2H), 5.70-5.45 (m, 2H),5.13 (d, J=14.5 Hz, 1H), 4.59 (dd, J=13.6, 5.4 Hz, 4H), 1.83 (s, 3H),1.45 (s, 3H), 1.03 (d, J=7.3 Hz, 3H).

Examples 91 and 92: Preparation of(1R,2S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamideand(1S,2S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C91 and C92)

A mixture of(1R,2S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(B) and(1S,2S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C) (25 mg, 0.0.56 mmol), prepared according to Example 90, wasdissolved in CH₃CN (3 mL) and added MgBr2 (38 mg, 0.206 mmol) andstirred at 50° C. for 2 h. Reaction mixture was quenched with water (1mL) to form clear solution, filtered and the residue was taken up inMeOH. The crude product was purified by reverse phase prep-HPLC with50-100% CH₃CN in water to afford the desired products,(1R,2S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamideand(1S,2S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.

(1R,2S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C91): MS (m/z): 445.1 [M+H]+. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.35(s, 1H), 8.37 (s, 1H), 7.44 (td, J=9.2, 8.8, 6.5 Hz, 1H), 6.97 (ddt,J=13.0, 8.5, 3.0 Hz, 2H), 5.67 (dd, J=11.2, 2.5 Hz, 1H), 5.39 (dd,J=11.2, 4.1 Hz, 1H), 5.11 (d, J=14.3 Hz, 1H), 4.60 (d, J=6.0 Hz, 2H),4.51 (d, J=14.2 Hz, 1H), 3.93 (ddd, J=6.7, 4.1, 2.6 Hz, 1H), 1.76 (s,3H), 1.42 (s, 3H), 1.33 (d, J=6.6 Hz, 3H).(1S,2S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C92): MS (m/z): 445.1 [M+H]+. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.35(s, 1H), 8.37 (s, 1H), 7.52-7.32 (m, 1H), 6.97 (ddt, J=11.2, 8.6, 3.0Hz, 2H), 5.67 (dd, J=11.2, 2.5 Hz, 1H), 5.39 (dd, J=11.2, 4.1 Hz, 1H),5.11 (d, J=14.2 Hz, 1H), 4.60 (d, J=5.9 Hz, 2H), 4.51 (d, J=14.3 Hz,1H), 3.93 (ddd, J=6.6, 4.1, 2.5 Hz, 1H), 1.76 (s, 3H), 1.42 (s, 3H),1.33 (d, J=6.6 Hz, 3H).

Examples 93 and 94: Preparation of(1S,2R)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamideand(1R,2S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C93 and C94)

A mixture of(1S,2R)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(A) and(1R,2S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(15 mg, 0.028 mmol), prepared according to Example 90, was dissolved inEtOH (3 mL) and added 10% Pd—C (6 mg, 0.006 mmol). Hydrogenolysis wasperformed with H₂ balloon at rt for 7 hrs. Reaction mixture was filteredthrough pad of Celite. Filtrate was collected and concentrated todryness. The residue was taken up in MeOH and was purified with reversephase prep-HPLC with 50-100% CH₃CN in water with 0.1% TFA to afford thedesired product(1S,2R)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamideand(1R,2S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.

(1S,2R)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C93): MS (m/z): 447.2 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 10.45(s, 1H), 8.32 (s, 1H), 7.44 (d, J=7.6 Hz, 1H), 6.97 (t, J=9.9 Hz, 3H),5.00-4.43 (m, 4H), 1.88-1.77 (m, 3H), 1.68 (s, 2H), 1.64-1.47 (m, 2H),1.39 (s, 3H), 1.12 (d, J=6.9 Hz, 3H).

(1R,2S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C94): MS (m/z): 447.1 [M+H]+. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 10.45(s, 1H), 8.32 (s, 1H), 7.44 (q, J=9.3, 8.5 Hz, 1H), 6.97 (t, J=10.0 Hz,2H), 4.83 (d, J=14.6 Hz, 1H), 4.66 (d, J=14.6 Hz, 1H), 4.60 (d, J=5.9Hz, 2H), 3.74-3.30 (m, 1H), 1.74-1.52 (m, 4H), 1.39 (s, 3H), 1.30 (s,3H), 1.12 (d, J=6.9 Hz, 3H).

Example 95: Preparation of(1S,2S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C95)

(1S,2S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5,5-trimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C) (20 mg, 0.037 mmol), prepared according to Example 90, was dissolvedin EtOH (3 mL) and added 10% Pd—C (8 mg, 0.0075 mmol). Hydrogenolysiswas performed with H2 balloon at rt for 7 hrs. Reaction mixture wasfiltered through pad of Celite. Filtrate was collected and concentratedto dryness. The residue was taken up in MeOH and was purified withreverse phase prep-HPLC with 50-100% CH₃CN in water with 0.1% TFA toafford the desired product(1S,2S)—N-(2,4-difluorobenzyl)-8-hydroxy-2,5,5-trimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.MS (m/z): 447.1 [M+H]+. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.57-8.18(m, 1H), 7.45 (s, 1H), 7.01 (d, J=22.1 Hz, 2H), 6.77 (s, 1H), 5.78-5.26(m, 1H), 5.19-4.14 (m, 4H), 3.97 (s, 1H), 1.87 (s, 4H), 1.82-1.67 (m,3H), 1.46-1.31 (m, 3H), 1.30 (s, 3H).

Example 96: Preparation of(1R,2S,5S)—N-(2,4-difluorobenzyl)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C96)

Step 1: Synthesis of methyl3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate

To a stirred mixture of methyl3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate(8.0 g, 14.7 mmol) and but-3-en-2-ol (1.592 g, 22.1 mmol) in THE (75 mL)at room temperature was added triphenyl phosphine (5.79 g, 22.1 mmol).The resulting mixture was cooled to 0° C., diisopropyl azodicarboxylate(4.46 g, 22.1 mmol) was added, the newly formed mixture was stirred at0° C. for 10 min before it was removed from the cooling bath and stirredat room temperature for 1 hour. The reaction was then filtered through apad of silica gel, rinsed with 60% EtOAc/Hexane, the filtrate was mixedwith silica gel, concentrated and purified by normal phasechromatography. LCMS-ESI+ (m/z): calcd H+ for C31H33F2N3O7, Theoretical:597.23, Found: 597.87.

Step 2: Synthesis of3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid

Methyl3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate(10.0 g, 16.7 mmol) was dissolved in a mixture of MeOH (96 mL), THE (48mL) and water (48 mL). To this stirred mixture was added LiOH—H₂O (4.21g, 100 mmol). The resulting mixture was heated to 60° C. for 6 hours.The reaction was then cooled to room temperature, concentrated, theresidue was diluted with EtOAc, acidified to pH ˜4 with 1N HCl, layerswere separated, the organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated. LCMS-ESI+(m/z): calcd H+ forC30H31F2N3O7, Theoretical: 583.21, Found: 583.868.

Step 3: Synthesis of tert-butyl(3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-2-(((S)-1-hydroxybut-3-en-2-yl)carbamoyl)-4-oxopyridin-1(4H)-yl)(but-3-en-2-yl)carbamate

To a mixture of3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylicacid (1.5 g, 2.57 mmol) and (2S)-2-aminobut-3-en-1-ol; hydrochloride(381 mg, 3.08 mmol) in DCM (12.0 mL) at room temperature was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (736 mg, 3.86 mmol)followed by 1-hydroxy-7-azabenzotriazole (525 mg, 3.86 mmol) and DIEA(1.329 g, 10.3 mmol). The resulting mixture was stirred at roomtemperature for overnight. The reaction was then diluted with DCM,washed with 10% citric acid, brine, dried over sodium sulfate, filteredand concentrated. Purified by normal phase chromatography.

Step 4: Synthesis of3-(benzyloxy)-1-(but-3-en-2-ylamino)-N⁵-(2,4-difluorobenzyl)-N²—((S)-1-hydroxybut-3-en-2-yl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide

tert-butyl(3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-2-(((S)-1-hydroxybut-3-en-2-yl)carbamoyl)-4-oxopyridin-1(4H)-yl)(but-3-en-2-yl)carbamate(700 mg, 1.07 mmol) was dissolved in DCM (10 mL) at room temperature andtreated with 4N HCl in 1,4-dioxane (10 mL) for 90 minutes. The reactionwas concentrated, coevaporated with ethyl acetate (×5) and thencoevaporated with acetonitrile (×5). Used directly in next step.

Step 5: Synthesis of5-(benzyloxy)-1-(but-3-en-2-yl)-N-(2,4-difluorobenzyl)-3-((S)-1-hydroxybut-3-en-2-yl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

3-(benzyloxy)-1-(but-3-en-2-ylamino)-N5-(2,4-difluorobenzyl)-N2-((S)-1-hydroxybut-3-en-2-yl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide(300 mg, 0.543 mmol) was dissolved in acetonitrile (1 mL). The resultingmixture was heated to 88° C. To this hot mixture was addedparaformaldehyde (42.9 mg, 1.36 mmol) followed by TFA (0.15 mL). Heatingcontinued for 15 hours. The reaction was then cooled to room temperatureand concentrated. The resulting residue was then dissolved in DMF (2mL), Benzyl bromide (111 mg, 0.652 mmol) and potassium carbonate (600mg, 4.34 mmol) were added sequentially. The resulting mixture was heatedto 70° C. for 2 hours. Then it was cooled to room temperature,partitioned between ethyl acetate and water, the organic layer waswashed with brine, dried over sodium sulfate, filtered and concentrated,purified by normal phase chromatography. LCMS-ESI+ (m/z): calcd H+ forC30H30F2N4O5, Theoretical: 564.22, Found: 565.102.

Step 6: Synthesis of5-(benzyloxy)-1-(but-3-en-2-yl)-N-(2,4-difluorobenzyl)-3-((S)-1-fluorobut-3-en-2-yl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

5-(benzyloxy)-1-(but-3-en-2-yl)-N-(2,4-difluorobenzyl)-3-((S)-1-hydroxybut-3-en-2-yl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(180 mg, 0.32 mmol) was dissolved in DCM (3 mL) and cooled to 0° C. Tothis cold mixture was added bis(2-methoxyethyl)aminosulfur trifluoride(423 mg, 1.91 mmol) dropwise. The reaction was removed from the coolingbath after addition and allowed to warm up to room temperature andstirred at that temperature for overnight. The reaction was then cooledback to 0° C., quenched with saturated sodium bicarbonate dropwise withvigorous stirring. The mixture was extracted with DCM. Organic layer waswashed with brine, dried over sodium sulfate, filtered and concentrated,purified by normal phase chromatography. LCMS-ESI+ (m/z): calcd H+ forC30H29F3N4O4, Theoretical: 566.21, Found: 567.120.

Step 7: Synthesis of(R,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-5-(fluoromethyl)-2-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

5-(benzyloxy)-1-(but-3-en-2-yl)-N-(2,4-difluorobenzyl)-3-((S)-1-fluorobut-3-en-2-yl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(100 mg, 0.177 mmol) was dissolved in DCE (3 ml). Hoveyda-Grubbs IIcatalyst (11.1 mg, 0.0177 mmol) was added. The resulting mixture waspurged with Argon for 5 minutes, then it was sealed and heated at 80° C.for overnight. The reaction was cooled to room temperature,concentrated, purified by normal phase chromatography. LCMS-ESI+ (m/z):calcd H+ for C28H25F3N4O4, Theoretical: 538.18, Found: 539.105.

Step 8: Synthesis of(1R,2S,5S)—N-(2,4-difluorobenzyl)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1R,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-5-(fluoromethyl)-2-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(20 mg, 0.0371 mmol) was dissolved in EtOH (20 mL) at room temperature.To this stirred mixture was added 10% Pd/C (4 mg). The resulting mixturewas degassed and flushed with nitrogen three times, degassed and flushedwith hydrogen three times and then it was hydrogenated under hydrogenballoon for 1 hour. The reaction was degassed and flushed with nitrogen,filtered through Celite. The filtrate was concentrated, purified byreverse phase prep HPLC. LCMS-ESI+ (m/z): calcd H+ for C21H21F3N4O4,Theoretical: 450.15, Found: 451.224. 1H NMR (400 MHz, DMSO-d6) δ 10.34(t, J=5.9 Hz, 1H), 8.34 (s, 1H), 7.42 (td, J=8.6, 6.6 Hz, 1H), 7.25(ddd, J=10.5, 9.3, 2.6 Hz, 1H), 7.07 (td, J=8.6, 2.6 Hz, 1H), 4.74 (s,2H), 4.71-4.43 (m, 6H), 1.94-1.81 (m, 1H), 1.77-1.65 (m, 1H), 1.61-1.39(m, 2H), 1.28 (d, J=7.1 Hz, 3H).

Example 97: Preparation of(1R,2S,5S)—N-(2,4-difluorobenzyl)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C97)

(1R,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-5-(fluoromethyl)-2-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(20 mg, 0.0371 mmol), prepared according to Example 96, was treated witha mixture of DCM (1.5 mL) and TFA (1.5 mL) at room temperature for 2hours. The reaction was concentrated and purified by reverse phase prepHPLC. LCMS-ESI+ (m/z): calcd H+ for C21H19F3N4O4, Theoretical: 448.14,Found: 449.179. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.19-10.11 (m, 1H),8.39 (s, 1H), 7.50-7.38 (m, 1H), 7.02-6.92 (m, 2H), 5.81 (dt, J=11.4,2.3 Hz, 1H), 5.66-5.59 (m, 1H), 5.54-5.39 (m, 1H), 5.13 (d, J=14.6 Hz,1H), 4.80-4.55 (m, 5H), 3.92-3.82 (m, 1H), 1.37 (d, J=6.7 Hz, 3H).

Example 98: Preparation of(1S,2R,5R)—N-(2,4-difluorobenzyl)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C98)

(1S,2R,5R)—N-(2,4-difluorobenzyl)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas made according to Example 96 except (2R)-2-aminobut-3-en-1-ol wasused instead of (2S)-2-aminobut-3-en-1-ol hydrochloride in Step 3.LCMS-ESI+ (m/z): calcd H+ for C21H21F3N4O4, Theoretical: 450.15, Found:451.12. 1H NMR (400 MHz, Acetonitrile-d3) δ 10.33 (s, 1H), 8.45 (s, 1H),7.44 (td, J=9.2, 8.8, 6.5 Hz, 1H), 7.06-6.86 (m, 2H), 4.79-4.39 (m, 7H),3.63-3.58 (m, 1H), 1.95-1.82 (m, 2H), 1.62 (dt, J=7.1, 3.5 Hz, 2H), 1.32(d, J=7.2 Hz, 3H).

Example 99: Preparation of(1S,2R,4S,5S)-4-fluoro-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C99)

Step 1: Synthesis of(1S,2R,4R,5R)-8-(benzyloxy)-5-(fluoromethyl)-4-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To(1S,2R,5R)-8-(benzyloxy)-5-(fluoromethyl)-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(116 mg, 0.208 mmol), prepared according to Example 50, in IPA (3 ml)was added PhSiH₃ (45.1 mg, 0.417 mmol), followed by Shenvi cat. (7.56mg, 0.0012 mmol), then the mixture was stirred under 02 for 24 h at roomtemperature. The reaction was quenched by adding 10% sodium thiosulfate,then it was extracted with EtOAc. The organic phase was washed withbrine and dried with MgSO₄. Solvent was removed under vacuo. Crudematerial was purified by silica gel column to obtain the title compound.MS (m/z) [M+H]⁺574.98.

Step 2: Synthesis of(1S,2R,4S,5S)-8-(benzyloxy)-4-fluoro-5-(fluoromethyl)-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To(1S,2R,4R,5R)-8-(benzyloxy)-5-(fluoromethyl)-4-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(30 mg, 0.0522 mmol) at 0° C. was added deoxofluor (2.7 N in toluene)(0.193 ml, 0.522 mmol) in DCM (1 ml) in a plastic vial. Then thereaction was stirred at room temperature for overnight. Reaction wasquenched with sat. NaHCO₃ at 0° C. and was extracted with DCM threetimes. The organic phase was washed with brine and dried with MgSO₄. Thecrude material was purified by silica gel column to obtain the titlecompound. MS (m/z) [M+H]⁺577.4.

Step 3: Synthesis of(1S,2R,4S,5S)-4-fluoro-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To(1S,2R,4S,5S)-8-(benzyloxy)-4-fluoro-5-(fluoromethyl)-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(66.2 mg, 0.115 mmol) was added TFA (0.5 ml) in toluene (0.5 ml) at roomtemperature. The reaction mixture was stirred at room temperature forovernight. Solvent was removed under vacuo and the crude material waspurified by prep-HPLC to obtain the title compound. MS (m/z)[M+H]⁺487.05. 1H NMR (400 MHz, Chloroform-d) δ 10.18 (d, J=5.1 Hz, 1H),8.59 (s, 1H), 6.80-6.56 (m, 2H), 5.41-5.21 (m, 1H), 5.12-4.88 (m, 2H),4.86-4.55 (m, 4H), 3.49 (s, 1H), 2.46-2.26 (m, 1H), 2.10-1.86 (m, 1H),1.56 (dd, J=7.3, 2.3 Hz, 3H), 1.54-1.14 (m, 1H).

Example 100: Preparation of(1S,2R,5S)-8-hydroxy-2,5,13-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C100)

Step 1: Synthesis of1-((R)-but-3-en-2-yl)-3-((S)-but-3-en-2-yl)-5-hydroxy-2-methyl-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

To a 20 mL microwave vial,3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-1-(((R)-but-3-en-2-yl)amino)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide(500 mg, 0.90 mmol, 1.0 eq), prepared in a manner similar to Example 24except using (S)-but-3-en-2-ol instead of but-3-en-2-ol in Step 2,acetaldehyde (0.5 mL, 8.97 mmol, 10 eq), dichloroethane (3.2 mL), andacetonitrile (3.2 mL), glacial acetic acid (354 μL, 6.14 mmol, 6.8 eq)and trifluoroacetic acid (354 μL, 4.58 mmol, 5.1 eq) were addedsequentially and the vials were immediately sealed and moved to a hotplate preheated to 90° C. The solutions were left to stir 90° C. for16.5 hours whereupon the vials were removed from heat allowed to cool toambient temperature. The contents of the vials were combined in a 100 mLErlenmeyer flask and saturated sodium bicarbonate (30 mL) and ethylacetate (20 mL) were added and let stir for 30 minutes. The layers werethen separated, the aqueous layer was extracted into ethyl acetate (2×20mL), and the combined organic extracts were dried over magnesiumsulfate, filtered, and concentrated. The resultant residue was purifiedvia flash column chromatography (0-100% EtOAc/Hexanes) affording1-((R)-but-3-en-2-yl)-3-((S)-but-3-en-2-yl)-5-hydroxy-2-methyl-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide.ES/MS: 491.171 [M+H]+.

Step 2: Synthesis of5-(benzyloxy)-1-((R)-but-3-en-2-yl)-3-((S)-but-3-en-2-yl)-2-methyl-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

To a 20 mL vial,1-((R)-but-3-en-2-yl)-3-((S)-but-3-en-2-yl)-5-hydroxy-2-methyl-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(123 mg, 0.25 mmol, 1.0 eq), potassium carbonate (178 mg, 1.3 mmol, 5.1eq), and dimethylformamide (6 mL) were added. To the suspension, benzylbromide (89 μL, 0.75 mmol, 3.0 eq) was added and the suspension was thenheated to 90° C. for 23 hours whereupon the reaction was removed fromheat allowed to cool to ambient temperature. The reaction mixture wasquenched with aqueous lithium chloride (10% w/w, 10 mL) and the layerswere separated. The aqueous layer was extracted into CH₂C₂ (2×15 mL),and the combined organic extracts were washed with water (2×15 mL),brine (15 mL), dried over magnesium sulfate, filtered, and concentrated.The resultant residue was purified via flash column chromatography(0-100% EtOAc/Hexanes) affording5-(benzyloxy)-1-((R)-but-3-en-2-yl)-3-((S)-but-3-en-2-yl)-2-methyl-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide.ES/MS: 581.182 [M+H]+.

Step 3: Synthesis of(1S,2R,5S)-8-(benzyloxy)-2,5,13-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To a 20 mL vial,5-(benzyloxy)-1-((R)-but-3-en-2-yl)-3-((S)-but-3-en-2-yl)-2-methyl-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(76 mg, 0.13 mmol, 1.0 eq), Hoyveda-Grubbs' catalyst second generation(8.3 mg, 0.013 mmol, 10 mol %), and dichloroethane (5 mL) were added.The solution was degassed and placed under an argon atmosphere (this wasdone in triplicate). The flask was then equipped with an air condenserand heated 80° C. for 21 hours whereupon it was removed from heat andallowed to cool to ambient temperature. The solids were removed viafiltration, the volatiles were removed in vacuo and the resultantresidue was purified via flash column chromatography (0-100%EtOAc/Hexanes) affording(1S,2R,5S)-8-(benzyloxy)-2,5,13-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.ES/MS: 553.183 [M+H]+.

Step 4: Synthesis of(1S,2R,5S)-8-hydroxy-2,5,13-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

To 1 dram vial,(1S,2R,5S)-8-(benzyloxy)-2,5,13-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(43 mg, 0.077 mmol, 1.0 eq), toluene (0.7 mL) and trifluoroacetic acid(0.7 mL) were added. The reaction was stirred as ambient temperature for4.5 hours whereupon the volatiles were removed in vacuo and theresultant residue was purified via preparative HPLC (0-100% CH₃CN/H₂Owith 0.1% TFA modifier) affording(1S,2R,5S)-8-hydroxy-2,5,13-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide.ES/MS: 463.215 [M+H]+. ¹H NMR (400 MHz, Chloroform-d) δ 10.25 (s, 1H),8.50 (d, J=1.1 Hz, 1H), 6.67 (t, J=8.1 Hz, 2H), 5.59 (d, J=11.5 Hz, 1H),5.50-5.39 (m, 1H), 5.35 (dt, J=11.6, 3.0 Hz, 1H), 5.18 (q, J=6.7 Hz,1H), 4.75-4.59 (m, 2H), 3.66 (dt, J=6.8, 3.3 Hz, 1H), 1.38 (dd, J=7.1,5.9 Hz, 6H), 1.28 (d, J=6.6 Hz, 3H).

Example 101: Preparation of(1S,2R,5S)-13-ethyl-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C101)

(1S,2R,5S)-13-ethyl-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamidewas prepared in a manner similar to Example 100, except using propanalinstead of acetaldehyde in Step 1. ES/MS: 477.186 [M+H]+. ¹H NMR (400MHz, Chloroform-d) δ 10.24 (s, 1H), 8.49 (s, 1H), 6.67 (t, J=8.1 Hz,2H), 5.66-5.50 (m, 1H), 5.50-5.42 (m, 1H), 5.34 (dt, J=11.6, 3.0 Hz,1H), 4.83 (t, J=7.3 Hz, 1H), 4.74-4.58 (m, 2H), 3.68 (dd, J=6.6, 3.3 Hz,1H), 1.52 (ddp, J=21.9, 14.5, 7.5 Hz, 2H), 1.38 (dd, J=10.5, 7.1 Hz,6H), 0.96 (t, J=7.4 Hz, 3H).

Example 102: Preparation of(1S,2R,5S)—N-((4-chloro-3,5-difluoropyridin-2-yl)methyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C102)

Step 1: Synthesis of (4-chloro-3,5-difluoropyridin-2-yl)methanamine

4 Å molecular sieve (1 g) was added to 4 mL 7 N NH₃ in MeOH. Stir for 2hours. Molecular sieve was removed by filtration. The filtrate wastreated with 4-chloro-3,5-difluoropicolinaldehyde (202 mg, 1.14 mmol) atroom temperature. The reaction mixture was stirred at r.t. overnight.Reaction mixture was cooled to 0° C. NaBH₄ (65 mg, 1.71 mmol) was addedat 0° C. Reaction mixture was then warmed to r.t. In 2 hrs the reactionwas quenched by sat. NaHCO₃ (10 mL). EtOAc (2×10 mL) was added forextraction of crude product. The organic layer was then treated with 1NHCl (10 mL). Aqueous layer was collected and was treated with NaHCO₃(sat) to make pH=8. Me-THF (1×10 mL) was used for extraction of product.The organic phase was separated and concentrated to dryness to affordproduct, which can be used directly without further purification. MS(m/z): 179.0 [M+H]+.

Step 2: Synthesis of(1S,2R,5S)-8-(benzyloxy)-N-((4-chloro-3,5-difluoropyridin-2-yl)methyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxylicacid (150 mg, 0.379 mmol), prepared according to Example 63, wasdissolved in DMF (1 mL) at rt. DIEA (0.264 mL, 1.52 mmol) was addedunder argon atmosphere. The resulting reaction mixture was cooled to 0°C. Then HATU (216 mg, 0.569 mmol) was added. The resulting reactionmixture was then warmed up to rt and stirred at rt for 1 hr. To thisreaction mixture, was added a solution of(3-chloro-2,4-difluorophenyl)methanamine (102 mg, 0.569 mmol) in DMF(0.5 mL). The reaction mixture was then stirred at rt for 17 hrs.Reaction mixture was diluted with EtOAc (10 mL) and was treated with amixture of saturated aqueous NH₄Cl solution (10 mL) and water (10 mL).Organic phase was then washed with water (10 mL) and saturated brine (10mL) sequentially. Organic phase was then separated and concentrated. Theresidue was purified on silica gel column with 0-100% EtOAc/Hex toafford product. MS (m/z): 556.1 [M+H]+.

Step 3: Synthesis of(1S,2R,5S)—N-((4-chloro-3,5-difluoropyridin-2-yl)methyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,5S)-8-(benzyloxy)-N-((4-chloro-3,5-difluoropyridin-2-yl)methyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(100 mg, 0.180 mmol) was dissolved in toluene (2 mL) at rt. TFA (2 mL)was added carefully with stirring. The resulting reaction mixture wasstirred at rt for 17 hrs. Reaction mixture was then concentrated todryness. The residue was taken up in MeOH and was purified with reversephase prep-HPLC with 0-100% CH₃CN in water with 0.1% TFA to afford thedesired product. Lyophilization afforded product. MS (m/z): 466.2[M+H]+; ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.43 (s, 1H), 8.44 (s, 1H),8.39 (s, 1H), 5.67 (dt, J=11.4, 2.5 Hz, 1H), 5.40 (ddt, J=16.9, 10.3,5.3 Hz, 2H), 5.02 (d, J=14.3 Hz, 1H), 4.78 (dd, J=5.7, 1.8 Hz, 2H), 4.58(d, J=14.3 Hz, 1H), 3.84 (tt, J=6.7, 3.4 Hz, 1H), 1.35 (dd, J=7.1, 2.9Hz, 6H).

Example 103: Preparation of(1S,2R,5S)—N-(3-chloro-2,4,6-trifluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C103)

Step 1: Synthesis of (3-chloro-2,4,6-trifluorophenyl)methanamine

4 Å molecular sieve (1 g) was added to 4 mL 7N NH₃ in MeOH. Stir for 2hours. Molecular sieve was removed by filtration. The filtrate wastreated with 3-chloro-2,4,6-trifluorobenzaldehyde (1000 mg, 5.14 mmol)at room temperature. The reaction mixture was stirred at r.t. overnight.Reaction mixture was cooled to 0° C. NaBH₄ (292 mg, 7.71 mmol) was addedat 0° C. Reaction mixture was then warmed to r.t. In 2 hrs the reactionwas quenched by sat. NaHCO₃ (10 mL). EtOAc (2×10 mL) was added forextraction of crude product. The organic layer was then treated with 1NHCl (10 mL). Aqueous layer was collected and was treated with NaHCO₃(sat) to make pH=8. Me-THF (1×10 mL) was used for extraction of product.The organic phase was separated and concentrated to dryness to affordproduct, which can be used directly without further purification. MS(m/z): 196.0 [M+H]+.

Step 2: Synthesis of(1S,2R,5S)-8-(benzyloxy)-N-(3-chloro-2,4,6-trifluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,5S)-8-(Benzyloxy)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxylicacid (200 mg, 0.506 mmol), prepared according to Example 63, wasdissolved in DMF (1 mL) at rt. DIEA (0.35 mL, 2.02 mmol) was added underargon atmosphere. The resulting reaction mixture was cooled to 0° C.Then HATU (250 mg, 0.658 mmol) was added. The resulting reaction mixturewas then warmed up to rt and stirred at rt for 1 hr. To this reactionmixture, was added a solution of(3-chloro-2,4,6-trifluorophenyl)methanamine (148 mg, 0.759 mmol) in DMF(0.5 mL). The reaction mixture was then stirred at rt for 17 hrs.Reaction mixture was diluted with EtOAc (10 mL) and was treated with amixture of saturated aqueous NH₄Cl solution (10 mL) and water (10 mL).Organic phase was then washed with water (10 mL) and saturated brine (10mL) sequentially. Organic phase was then separated and concentrated. Theresidue was purified on silica gel column with 0-100% EtOAc/Hex toafford product. MS (m/z): 572.9 [M+H]+.

Step 3: Synthesis of(1S,2R,5S)—N-(3-chloro-2,4,6-trifluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1S,2R,5S)-8-(Benzyloxy)-N-(3-chloro-2,4,6-trifluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(130 mg, 0.227 mmol) was dissolved in DMF (2 mL) at rt. LiCl (58 mg,1.36 mmol) was added. The resulting reaction mixture was heated withstirring at 100° C. for 6 hrs. Reaction mixture was then diluted withEtOAc (10 mL) and was treated with NH₄Cl (saturated aq) (10 mL) and 1NHCl (10 mL). The organic phase was separated and washed with water (10mL) and brine (10 mL). Concentration of organic extraction afforded thecrude product. Further purification with silica gel column (0-100%EtOAc/Hex) afforded the product. MS (m/z): 483.2 [M+H]+; 1H NMR (400MHz, Acetonitrile-d3) δ 10.26 (s, 1H), 8.37 (s, 1H), 7.05 (td, J=9.5,2.2 Hz, 1H), 5.66 (dt, J=11.4, 2.4 Hz, 1H), 5.46-5.32 (m, 2H), 5.01 (d,J=14.4 Hz, 1H), 4.65 (d, J=6.0 Hz, 2H), 4.56 (d, J=14.4 Hz, 1H), 3.83(tt, J=7.0, 3.6 Hz, 1H), 1.37-1.28 (m, 6H).

Example 104: Preparation of(1′S,5′S)-8′-hydroxy-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-7′,9′-dihydro-5′H-spiro[cyclobutane-1,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamid(C104)

Step 1: Synthesis of di-tert-butyl1-(1-formylcyclobutyl)hydrazine-1,2-dicarboxylate

Cyclobutanecarbaldehyde (1.64 g, 19.5 mmol) anddi-tert-butyl-diazene-1,2-dicarboxylate (3 g, 13 mmol) were dissolved inDCM. Then L-Proline (0.15 g, 1.3 mmol) was added. The slurry was stirredat rt for 2 hr and then was heated at 40° C. for 5 hr. Solvent wasremoved via rotovap. The residue was partitioned between EtOAc (50 mL)and water (50 mL). Brine was added to facilitate the separation. Organicphase was separated and washed with water and brine. Organic phase wasseparated and concentrated to afford pale yellow solid. Purification onsilica gel column with 0-100% EtOAc in Hex afforded product. 1H NMR (400MHz, CD3CN) δ 9.99-9.39 (br, 1H), 7.69-6.55 (br, 1H), 2.48-2.20 (m, 4H),1.82 (d, J=15.2 Hz, 2H), 1.61-1.34 (m, 18H).

Step 2: Synthesis of di-tert-butyl1-(1-vinylcyclobutyl)hydrazine-1,2-dicarboxylate

To a suspension of methyltriphenylphosphonium iodide (5.56 g, 13.5 mmol)in THE (25 mL) at 0° C. was added KOtBu (1.51 g, 13.5 mmol). The mixturewas stirred for 30 min. A solution of di-tert-butyl1-(1-formylcyclobutyl)hydrazine-1,2-dicarboxylate (2.12 g, 6.74 mmol) inTHE (10 mL) was added dropwise over 10 min. The reaction mixture waswarmed to rt. After being stirring 17 h, the reaction mixture was cooledto 0° C. EtOAc (20 mL) was added. The resulting reaction mixture wastreated with saturated NH4Cl aqueous solution (10 mL) and water (10 mL).The organic phase was separated and the aqueous phase was extracted withEtOAc (2×10 mL). The combined organic phases were concentrated.Purification by silica gel column chromatography (0-50% EtOAc/hexanes)afforded product. 1H NMR (400 MHz, CD3CN) δ 7.01 (br, 1H), 6.14 (dd,J=17.4, 10.6 Hz, 1H), 5.31-4.97 (m, 2H), 2.53-2.22 (m, 2H), 2.17-1.99(m, 2H), 1.83-1.64 (m, 2H), 1.44 (d, J=16.0 Hz, 18H).

Step 3: Synthesis of 2-(1-vinylcyclobutyl)hydrazin-1-ium2,2,2-trifluoroacetate

Di-tert-butyl 1-(1-vinylcyclobutyl)hydrazine-1,2-dicarboxylate (1.25 g,4 mmol) was dissolved in DCM (15 mL) at rt and was cooled down withice-water bath under argon. TFA (15 mL) was added. The resultingreaction mixture was allowed to warm to rt and stir for 17 hr. Reactionmixture was then concentrated to dryness. The residue was place underhigh vac for 5 hrs to afford the product. MS (m/z): 113.0 [M+H]+.

Step 4: Synthesis of methyl3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((1-vinylcyclobutyl)amino)-1,4-dihydropyridine-2-carboxylate

2-(1-Vinylcyclobutyl)hydrazin-1-ium 2,2,2-trifluoroacetate (900 mg, 4mmol) was dissolved in MeOH (20 mL). Then NaHCO₃ (1.4 g, 16.8 mmol) wasadded as solid. Then methyl3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate(1.5 g, 3.35 mmol) was added as solid in one portion. Water (10 mL) wasadded. The resulting reaction mixture was heated at 55° C. for 17 hr.Then reaction mixture was diluted with EtOAc (20 mL) and was treatedwith brine (20 mL) and water (20 mL). Organic phase was separated andconcentrated to afford the product. MS (m/z): 542.0 [M+H]+.

Step 5: Synthesis of3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((1-vinylcyclobutyl)amino)-1,4-dihydropyridine-2-carboxylicacid

Methyl3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((1-vinylcyclobutyl)amino)-1,4-dihydropyridine-2-carboxylate(1.82 g, 3.36 mmol) was dissolved in MeOH (30 mL), water (15 mL) and THE(10 mL) at rt. LiOH (5M in water, 5.38 mL) was added. Reaction mixturewas stirred at rt for 20 hr. Reaction mixture was concentrated carefullyfor removal of MeOH. The residue was diluted and rinsed with some water(30 mL) and was acidified with 1N HCl to pH=3. EtOAc (50 mL) was addedfor extraction. Organic phase was separated. Aqueous layer was extractedwith more EtOAc (30 mL). The combined organic phases were washed withwater and brine. The separated organic phase was dried over Na₂SO⁴,filtered and concentrated to afford the acid product. MS (m/z): 527.9[M+H]+.

Step 6: Synthesis of(S)-3-(benzyloxy)-N2-(but-3-en-2-yl)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1-((1-vinylcyclobutyl)amino)-1,4-dihydropyridine-2,5-dicarboxamide

3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((1-vinylcyclobutyl)amino)-1,4-dihydropyridine-2-carboxylicacid (1.71 g, 3.24 mmol) was dissolved in DMF (20 mL) at rt under argon.DIEA (2.82 mL, 16.2 mmol) was added. Reaction mixture was cooled downwith ice-water bath. HATU (1.946 g, 4.86 mmol) was then added. Letreaction mixture be stirred at low temp for 5 min then the cold bath isremoved. Reaction mixture was stirred at rt for 1 h. Then(S)-but-3-en-2-amine HCl salt (0.816 g, 7.59 mmol) was added at rt inone portion. Reaction mixture was stirred at rt for 17 hr. Reactionmixture was then diluted with EtOAc (50 ml) and washed sequentially withNaHCO₃ (sat) (20 mL)/water (20 mL), NH4Cl (20 mL), water (20 mL) andbrine (20 mL). Organic phase was dried over Na₂SO₄ and filtered. Thefiltrate was concentrated to afford product. MS (m/z): 581.0 [M+H]+.

Step 7: Synthesis of(S)-3-(but-3-en-2-yl)-5-hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-(1-vinylcyclobutyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

(S)-3-(benzyloxy)-N2-(but-3-en-2-yl)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1-((1-vinylcyclobutyl)amino)-1,4-dihydropyridine-2,5-dicarboxamide(1.8 g, 3.1 mmol) was dissolved in ACN (6 mL) and DCE (6 mL).Paraformaldehyde (245 mg, 7.75 mmol) was added. AcOH (0.86 mL) and TFA(0.86 mL) were added dropwise sequentially without stirring. Reactionwas heated under argon to 85° C. with stirring and kept under thatcondition for 24 hrs. Reaction mixture was then concentrated to dryness.The residue was purified on silica gel column with 0-100% EtOAc/Hex toafford product. MS (m/z): 503.2 [M+H]+.

Step 8: Synthesis of(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-(1-vinylcyclobutyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

(S)-3-(but-3-en-2-yl)-5-hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-(1-vinylcyclobutyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(1.16 g, 2.31 mmol) was dissolved in DMF (5 mL) at rt. K₂CO₃ (2.44 g,17.7 mmol) was added. Then BnBr (1.38 g, 8.08 mmol) was added. Reactionmixture was heated to 73° C. (bath temp) for 5 hrs. Reaction mixture wasdiluted with EtOAc (50 mL) and was treated with water (20 mL). Organicphase was separated. Aqueous layer was extracted with EtOAc (20 mL). Thecombined organic phases were washed with water and brine. Concentrationof organic phase gave the crude product. Further purification on silicagel column with 0-100% EtOAc/Hex afforded product. MS (m/z): 593.1[M+H]+.

Step 9: Synthesis of(1′S,5′S)-8′-(benzyloxy)-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-7′,9′-dihydro-5′H-spiro[cyclobutane-1,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide

(S)-5-(benzyloxy)-3-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-(1-vinylcyclobutyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(0.5 g, 0.85 mmol) was dissolved in dichloroethane (15 mL). The solutionwas bubbled with argon gas for 10 min. Grubbs catalyst M202 (211 mg,0.22 mmol) was added. Then the purging with argon was applied again for10 min. The reaction mixture was heated at 80° C. under argon for 24hrs. Another round of addition of Grubbs M202 (211 mg, 0.22) wasapplied, followed by purging with argon gas for 10 min. Reaction mixturewas heated again at 80° C. for 24 hrs. Reaction mixture was thenconcentrated to dryness. The residue was purified on silica gel columnwith 0-100% EtOAc/Hex to afford product. MS (m/z): 565.1 [M+H]+.

Step 10: Synthesis of(1′S,5′S)-8′-hydroxy-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-7′,9′-dihydro-5′H-spiro[cyclobutane-1,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide

(1'S,5′S)-8′-(benzyloxy)-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-7′,9′-dihydro-5′H-spiro[cyclobutane-1,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(12 mg, 0.0213 mmol) was dissolved in toluene (8 mL). TFA (9 mL) wasadded at rt. The resulting reaction mixture was stirred at rt for 17 hr.Reaction mixture was then concentrated to dryness. The residue waspurified with reverse phase prep-HPLC with 0-100% CH₃CN in water with0.1% TFA to afford the desired product. Lyophilization afforded product.MS (m/z): 475.2 [M+H]+. ¹H NMR (400 MHz, CD3CN) δ 10.23 (s, 1H), 8.48(s, 1H), 7.05-6.82 (m, 2H), 6.05 (dd, J=11.8, 2.6 Hz, 1H), 5.64 (dd,J=11.8, 2.3 Hz, 1H), 5.43-5.23 (m, 1H), 5.00 (d, J=14.4 Hz, 1H),4.73-4.59 (m, 2H), 4.55 (d, J=14.4 Hz, 1H), 2.45-2.32 (m, 1H), 2.32-2.22(m, 1H), 1.86-1.57 (m, 4H), 1.32 (d, J=7.3 Hz, 3H).

Example 105: Preparation of(1′S,5′S)-8′-hydroxy-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-4′,5′,7′,9′-tetrahydro-3′H-spiro[cyclobutane-1,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(C105)

(1′S,5′S)-8′-(benzyloxy)-5′-methyl-7′,9′-dioxo-N-(2,4,6-trifluorobenzyl)-7′,9′-dihydro-5′H-spiro[cyclobutane-1,2′-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10′-carboxamide(10 mg, 0.0177 mmol), prepared according to Example 104, was dissolvedin MeOH (10 mL). Pd/C (10%) (12 mg) was added. The reaction mixture wasstirred under a H₂ balloon atmosphere for 6 hrs. Reaction mixture wasthen filtered to remove the catalyst. The filtrate was concentrated todryness. The residue was purified with reverse phase prep-HPLC with0-100% CH₃CN in water with 0.1% TFA to afford the desired product.Lyophilization afforded product. MS (m/z): 477.1 [M+H]+. 1H NMR (400MHz, CD3CN) δ 10.35 (s, 1H), 8.50 (s, 1H), 6.87 (t, J=8.5 Hz, 2H),4.64-4.57 (m, 4H), 4.45 (d, J=14.6 Hz, 1H), 2.21-2.00 (m, 4H), 1.85 (dt,J=15.4, 5.0 Hz, 2H), 1.74-1.39 (m, 4H), 1.23 (d, J=6.7 Hz, 3H).

Example 106: Preparation of(1S,2S,5S)-2-ethyl-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C106)

The reaction mixture of(1S,2S,5S)-8-(benzyloxy)-2-ethyl-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(8 mg, 0.0145 mmol), prepared as the minor product (B) according to Step2 of Example 72, and lithium chloride (6.1 mg, 0.145 mmol) in DMF (1 mL)was stirred at 100° C. overnight. The reaction mixture was filtered,loaded on reverse phase HPLC, eluting with 5-100% acetonitrile in waterto give the title product. MS (m/z) 463.20 [M+H]⁺. 1H NMR (400 MHz,Methanol-d4) δ 8.51 (s, 1H), 6.98-6.86 (m, 2H), 5.74 (ddd, J=12.3, 3.1,1.8 Hz, 1H), 5.57 (ddd, J=12.4, 4.7, 2.1 Hz, 1H), 5.45-5.38 (m, 1H),5.11 (d, J=14.4 Hz, 1H), 4.78 (d, J=14.4 Hz, 1H), 4.69 (d, J=2.3 Hz,2H), 4.47 (dd, J=6.6, 3.1 Hz, 1H), 1.61 (tt, J=12.3, 7.3 Hz, 1H), 1.41(d, J=7.3 Hz, 3H), 1.24 (ddd, J=13.3, 9.4, 7.0 Hz, 1H), 0.82 (t, J=7.3Hz, 3H).

Example 107: Preparation of(1S,2R,5S)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2-(2,2,2-trifluoroethyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C107)

Step 1: Synthesis of di-tert-butyl1-(4,4,4-trifluoro-1-oxobutan-2-yl)hydrazine-1,2-dicarboxylate

4,4,4-Trifluorobutanal (2.46 g, 19.5 mmol) anddi-tert-butyl-diazene-1,2-dicarboxylate (3 g, 13 mmol) were dissolved inDCM (100 mL). Then L-proline (0.15 g, 1.3 mmol) was added. The slurrywas stirred at rt for 2 h and then was heated at 40° C. for 17 h.Solvent was removed. The residue was purified on silica gel column with0-100% EtOAc in hex to afford product. 1H NMR (400 MHz, CD3CN) δ 9.66(d, J=12.9 Hz, 1H), 7.70-7.37 (m, 1H), 4.67-4.62 (m, 1H), 2.87 (dtt,J=15.5, 12.0, 5.8 Hz, 1H), 2.63-2.44 (m, 1H), 1.51-1.40 (m, 18H).

Step 2: Synthesis of di-tert-butyl 1-(5,5,5-trifluoropent-1-en-3-yl)hydrazine-1,2-dicarboxylate

To a suspension of methyltriphenylphosphonium iodide (7.03 g, 17 mmol)in THE (100 mL) at 0° C. was added KOtBu (2.0 g, 17.8 mmol). The mixturebecame a yellow suspension and was stirred for 30 min. A solution ofdi-tert-butyl1-(4,4,4-trifluoro-1-oxobutan-2-yl)hydrazine-1,2-dicarboxylate (2.5 g,7.02 mmol) in THE (27 mL) was added dropwise over 10 min. The reactionmixture was warmed to rt. After being stirring 17 h, the reactionmixture was cooled to 0° C. and EtOAc (20 mL) was added. The resultingreaction mixture was treated with saturated NH4Cl aqueous solution (10mL) and water (10 mL). The organic phase was separated and the aqueousphase was extracted with EtOAc (2×10 mL). The combined organic phaseswere concentrated to afford an orange foamy oil. Purification by silicagel column chromatography (0-50% EtOAc/hexanes) afforded product. 1H NMR(400 MHz, CD3CN) δ 7.31-6.47 (m, 1H), 6.05-5.78 (m, 1H), 5.38-5.12 (m,2H), 4.94 (s, 1H), 2.83-2.36 (m, 2H), 1.45 (d, J=3.4 Hz, 18H).

Step 3: Synthesis of (5,5,5-tri fluoropent-1-en-3-yl)hydrazinetrifluoroacetic acid salt

Di-tert-butyl1-(5,5,5-trifluoropent-1-en-3-yl)hydrazine-1,2-dicarboxylate (1.76 g,4.97 mmol) was dissolved in DCM (40 mL) at rt and was cooled down withice-water bath under argon. TFA (20 mL) was added. The resultingreaction mixture was allowed to warm to rt and stirred for 17 h.Reaction mixture was then concentrated to dryness and the residue wasplaced under high vac for 5 h to afford the product. MS (m/z) 155.1[M+H]+.

Step 4: Synthesis of methyl3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((5,5,5-trifluoropent-1-en-3-yl)amino)-1,4-dihydropyridine-2-carboxylate

(5,5,5-trifluoropent-1-en-3-yl)hydrazine trifluoroacetic acid salt (1.32g, 4.96 mmol) was dissolved in MeOH (30 mL). Then NaHCO₃ (3.474 g, 41.4mmol) was added as solid and some bubbles appeared. Methyl3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate(1.85 g, 4.14 mmol) was added as solid in one portion. Water (15 mL) wasadded. The resulting reaction mixture was heated at 55° C. for 17 h.Then reaction mixture was diluted with EtOAc (20 mL) and was treatedwith brine (20 mL) and water (20 mL). Organic phase was separated andconcentrated to afford the product. MS (m/z) 584.3 [M+H]+.

Step 5: Synthesis of3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((5,5,5-trifluoropent-1-en-3-yl)amino)-1,4-dihydropyridine-2-carboxylicacid

Methyl3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((5,5,5-trifluoropent-1-en-3-yl)amino)-1,4-dihydropyridine-2-carboxylate(2.41 g, 4.13 mmol) was dissolved in MeOH (30 mL), water (10 mL) and THE(15 mL) at rt. LiOH (5 M in water) (6.61 mL, 33.05 mmol) was added.Reaction mixture was stirred at rt for 20 hr. Reaction mixture wasconcentrated carefully for removal of MeOH. The residue was diluted andrinsed with some water (30 mL), then acidified with 1N HCl to pH=3.EtOAc (50 mL) was added and the organic phase was extracted with EtOAc(2×30 mL). The combined organic phases were washed with water and brine.The separated organic phase was dried over Na2SO4, filtered andconcentrated to afford the product. MS (m/z) 570.2 [M+H]+.

Step 6: Synthesis of(3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1-((5,5,5-trifluoropent-1-en-3-yl)amino)-1,4-dihydropyridine-2,5-dicarboxamide

3-(Benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1-((5,5,5-trifluoropent-1-en-3-yl)amino)-1,4-dihydropyridine-2-carboxylicacid (2.35 g, 4.13 mmol) was dissolved in DMF (20 mL) at rt under argon.DIEA (3.59 mL, 20.6 mmol) was added and the reaction mixture was cooledto 0° C. HATU (2.478 g, 6.19 mmol) was then added and the reactionmixture was stirred at this temperature for 5 min before the cold bathwas removed. Reaction mixture was stirred at rt for 1 h. Then the(S)-methyl allylamine HCl salt (1.05 g, 9.78 mmol) was added at rt inone portion. Reaction mixture was stirred at rt for 17 h. Reactionmixture was then diluted with EtOAc (50 mL) and washed sequentially withNaHCO₃ (sat) (20 mL), water (20 mL), NH4Cl (20 mL), water (20 mL) andbrine (20 mL). Organic phase was dried over Na2SO4 and filtered. Thefiltrate was concentrated to afford product. MS (m/z) 623.3 [M+H]+.

Step 7: Synthesis of3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1-(((R)-5,5,5-trifluoropent-1-en-3-yl)amino)-1,4-dihydropyridine-2,5-dicarboxamide

A mixture of two diastereomers of3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1-((5,5,5-trifluoropent-1-en-3-yl)amino)-1,4-dihydropyridine-2,5-dicarboxamidewas subject to chiral SFC with ADH-25 and elution with IPA-NH3 to afford3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1-(((R)-5,5,5-trifluoropent-1-en-3-yl)amino)-1,4-dihydropyridine-2,5-dicarboxamideas the first peak. MS (m/z) 623.3 [M+H]+.

Step 8: Synthesis of3-((S)-but-3-en-2-yl)-5-hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-((R)-5,5,5-trifluoropent-1-en-3-yl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

3-(Benzyloxy)-N2-((S)-but-3-en-2-yl)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1-(((R)-5,5,5-trifluoropent-1-en-3-yl)amino)-1,4-dihydropyridine-2,5-dicarboxamide(0.5 g, 0.803 mmol) was dissolved in ACN (3 mL) and DCE (3 mL).Paraformaldehyde (63.4 mg, 2.01 mmol) was added. AcOH (0.223 mL) and TFA(0.223 mL) were added dropwise sequentially without stirring. Reactionwas heated under argon to 85° C. with stirring and kept under thatcondition for 24 h. Reaction mixture was then concentrated to dryness.The residue was purified on silica gel column with 0-100% EtOAc/Hex toafford product. MS (m/z) 545.1 [M+H]+.

Step 9: Synthesis of5-(benzyloxy)-3-((S)-but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-((R)-5,5,5-trifluoropent-1-en-3-yl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide

3-((S)-But-3-en-2-yl)-5-hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-((R)-5,5,5-trifluoropent-1-en-3-yl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(70 mg, 0.129 mmol) was dissolved in DMF (5 mL) at rt. K2CO3 (136 mg,0.98 mmol) was added. Then benzyl bromide (77 mg, 0.45 mmol) was added.The reaction mixture was heated to 73° C. (bath temp) for 5 h. Reactionmixture was diluted with EtOAc (50 mL) and was treated with water (20mL). Organic phase was separated and the aqueous layer was extractedwith EtOAc (20 mL). The combined organic phases were washed with waterand brine. Concentration of organic phase gave the crude product.Further purification on silica gel column with 0-100% EtOAc/Hex affordedproduct. MS (m/z) 635.0 [M+H]+.

Step 10: Synthesis of(1S,2R,5S)-8-(benzyloxy)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2-(2,2,2-trifluoroethyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

5-(Benzyloxy)-3-((S)-but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1-((R)-5,5,5-trifluoropent-1-en-3-yl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide(40 mg, 0.063 mmol) was dissolved in dichloroethane (5 mL). Grubbscatalyst M720 (8.14 mg, 0.0124 mmol) was added. Then purging with argonwas applied for 10 min. The reaction mixture was heated at 80° C. underargon for 24 h. Reaction mixture was then concentrated to dryness. Theresidue was purified on silica gel column with 0-100% EtOAc/Hex toafford product. MS (m/z) 607.0 [M+H]+.

Step 11: Synthesis of(1S,2R,5S)-8-hydroxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2-(2,2,2-trifluoroethyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide

(1R,2R,5S)-8-(Benzyloxy)-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2-(2,2,2-trifluoroethyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(38 mg, 0.0627 mmol) was dissolved in DMF (3 mL). LiCl (34.2 mg, 0.807mmol) was added at rt. The resulting reaction mixture was heated at 100°C. with stirring for 7 h. Reaction mixture was then diluted with EtOAc(10 mL) and then treated with 1N HCl (10 mL). The organic phase wasseparated and washed with water (10 mL) and brine (10 mL). The organicphase was concentrated to afford a residue, which was purified byreverse phase prep-HPLC with 0-100% CH3CN in water with 0.1% TFA toafford the desired product. Lyophilization afforded desired product. MS(m/z) 517.2 [M+H]+. 1H NMR (400 MHz, CD3CN) δ 10.18 (s, 1H), 8.43 (s,1H), 6.88 (t, J=8.5 Hz, 2H), 5.79 (dt, J=11.8, 2.6 Hz, 1H), 5.50 (dt,J=11.6, 3.1 Hz, 1H), 5.38 (h, J=6.9 Hz, 1H), 4.98 (d, J=14.6 Hz, 1H),4.71-4.56 (m, 3H), 4.17 (tq, J=6.1, 3.0 Hz, 1H), 2.68 (dddd, J=15.8,13.2, 10.3, 5.4 Hz, 2H), 1.36 (d, J=7.4 Hz, 3H).

Examples 108 and 109: Preparation of(1R)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamideand(1S)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C108 and C109)

Prepared according to Example 2 of WO2019160783 using(2,4,6-trifluorophenyl)methanamine instead of(2,4-difluorophenyl)methanamine in Step 3. Separated by chiral SFC using40% methanol to give Peak 1 and Peak 2.

Peak 1: MS-ESI (m/z) 423.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.23 (brs, 1H), 8.55 (s, 1H), 6.66 (t, J=8.0 Hz, 2H), 4.82-4.61 (m, 3H),4.42-4.36 (m, 2H), 3.37 (s, 2H), 3.22-3.17 (m, 1H), 2.23-2.20 (m, 1H),1.95-1.89 (m, 1H), 1.77-1.74 (m, 1H), 1.60-1.57 (m, 1H).

Peak 2: MS-ESI (m/z) 423.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.25 (brs, 1H), 8.58 (s, 1H), 6.66 (t, J=8.0 Hz, 2H), 4.82-4.61 (m, 3H),4.44-4.36 (m, 2H), 3.39 (s, 2H), 3.22-3.18 (m, 1H), 2.23-2.20 (m, 1H),1.95-1.89 (m, 1H), 1.76-1.74 (m, 1H), 1.61-1.57 (m, 1H).

Example 110: HIV MT-4 Antiviral and Cytotoxicity Assay Antiviral Assayin MT-4 Cells

Compounds were tested in a high-throughput 384-well assay format fortheir ability to inhibit the replication of HIV-1 (IIIB) in MT-4 cells.Compounds were serially diluted (1:3) in DMSO on 384-well polypropyleneplates and further diluted 200-fold into complete RPMI media (10% FBS,1% P/S) using the Biotek Micro Flow and Labcyte ECHO acoustic dispenser.Each plate contained up to 8 test compounds, with negative (No DrugControl) and 5 μM AZT positive controls. MT-4 cells were pre-infectedwith 10 μL of either RPMI (mock-infected) or a fresh 1:250 dilution ofHIV-1 IIIB concentrated virus stock. Infected and uninfected MT-4 cellswere further diluted in complete RPMI media and added to each plateusing a Micro Flow dispenser. After 5 days incubation in a humidifiedand temperature controlled incubator (37° C.), Cell Titer Glo (Promega)was added to the assay plates and chemiluminescence read using anEnvision plate-reader. EC₅₀ values were defined as the compoundconcentration that causes a 50% decrease in luminescence signal, andwere calculated using a sigmoidal dose-response model to generate curvefits.

Cytotoxicity Assay in MT-4 Cells

Assays were performed as above except uninfected MT-4 cells were addedto each well containing test compound. In addition, 10 μM puromycin wasadded to the last column of each assay plate to assess a base level ofcytotoxicity.

Example 111: HIV MT-4 Serum Shift Antiviral Reporter Assay

To quantify the amount of protein binding to human serum, compounds wereserially diluted (1:3) in DMSO and acoustically transferred onto384-well assay plates via a Labcyte ECHO robot. Each plate contained upto 8 test compounds, including negative and positive controls, (DMSO, 5μM AZT respectively). Assay plates were prepared in duplicate, andtested in either CCM (cell culture media) or HS/CCM (human serum/cellculture media). MT-4 cells were first pre-infected with pLai RLucreporter virus for 2 h at 37° C., then further diluted in either CCM(RPMI media, 10% FBS, 1% P/S) or HS/CCM (RPMI media, 10% FBS, 50% HS, 1%P/S), and subsequently added to each plate using a Biotek Micro Flowdispenser. After a 72-h incubation in a humidified and temperaturecontrolled incubator (37° C.), Renilla Glo (Promega) was added to allassay plates and chemiluminescence read using an Envision plate-reader.EC₅₀ values were defined as the compound concentration that causes a 50%decrease in luminescence signal, and were calculated using a sigmoidaldose-response model to generate curve fits. To determine the amount ofprotein binding, EC₅ fold shifts (or EC₅₀ shifts) were calculated bydividing EC₅₀ (HS/CCM)/EC₅₀ (CCM).

Compounds of the present disclosure demonstrate antiviral activity inthis assay as depicted in Table 1 below. Accordingly, the compounds ofthe embodiments disclosed herein may be useful for treating theproliferation of the HIV virus, treating AIDS, or delaying the onset ofAIDS or ARC symptoms.

TABLE 1 RLUC MT4 RLUC 50% Example EC₅₀ CC₅₀ CCM HS RLUC No. (nM) (nM)(nM) (nM) Shift C1 20 10057 3.18 30.2 9 C2 18 12797 2.86 47.9 17 C3 1.713396 0.39 2.72 7 C4 1.2 11965 0.54 6.08 11 C5 3.4 14173 0.42 40.4 96 C67.5 9880 3.5 23.1 7 C7 2.1 9188 0.35 172 485 C8 1.8 4717 0.55 16.4 30 C925327 C10 1.8 7572 0.4 339 854 C11 1.1 9929 0.27 7.32 27 C12 3.4 108450.77 273 356 C13 1.3 8872 0.25 4.07 16 C14 2.0 8056 0.71 31.1 44 C15 1.99972 C16 1.1 11436 0.32 19.4 60 C17 0.91 11186 0.16 7.12 44 C18 4.313377 C19 1.1 10209 0.41 60.3 148 C20 3.5 16591 C21 1.7 11696 0.23 98.1425 C22 2.2 16331 C23 2.5 50000 0.29 14.5 51 C24 0.98 11413 0.44 328 747C25 1.0 17448 0.47 68 147 C26 2.4 28143 0.63 349 552 C27 1.3 9549 0.55594 1072 C28 1.4 6872 0.33 319 979 C29 0.71 18657 0.31 169 543 C30 1.335827 0.32 29 89 C31 0.9 7854 0.41 328 798 C32 2.4 28033 0.55 1.039 1.9C33 4.0 32884 1.8 4.3 2.3 C34 1.4 8361 0.59 938 1587 C35 1.6 29913 1.3188 149 C36 1.6 16563 C37 1.3 8567 0.87 325 375 C38 1.5 13570 1.1 17 14C39 3.5 20277 0.93 4.7 5 C40 2.1 15990 1.3 139 103 C41 1.2 14235 0.7168.6 97 C42 2.2 7033 2.47 1881 761 C43 5.3 6106 1.68 544 324 C44 1.214955 C45 1.8 11014 C46 1.6 27042 0.44 468 1071 C47 1.8 11488 1.71 196114 C48 1.5 50000 C49a 1.2 11320 0.64 140 220 C49b 1.9 8926 1.0 462 450C50 0.85 13332 0.37 850 2322 C51 1.3 9811 2.3 408 180 C52 1.5 9215 0.77472.6 614 C53 1.3 9013 0.55 350.1 642 C54 2.3 47389 0.63 72.36 114 C551.3 29525 0.71 515.1 730 C56 1.1 10116 0.52 24.9 48 C57 1.2 8931 0.2711.6 44 C58 1.5 11251 0.28 293.6 1034 C59 2.8 50000 C60 95.7 50000 42.64103.6 2 C61 2.8 50000 0.76 1.6 2 C62 1.4 50000 C63 C64 0.8 11354 0.27150.3 549 C65 1.8 15419 0.44 63.8 146 C66 1.4 10440 0.5 178.7 357 C671.9 25509 0.51 35.3 69 C68 1.6 17269 0.82 291.3 356 C69 1.5 38937 0.55145.5 264 C70 1.2 11567 0.54 11.5 21 C71 C72 0.5 13830 0.33 250.9 772C73 0.8 7645 0.63 275.7 440 C74 0.9 6813 0.47 325.3 695 C75 2.0 108681.02 277.2 273 C76 1.0 16378 0.42 265.2 632 C77 2.0 15741 1.14 295.9 260C78 1.6 13658 0.42 1037.5 2470 C79 4.6 50000 1.81 638.3 352 C80 8.125356 1.24 809.7 652 C81 1.5 13709 0.48 723.0 1509 C82 1.3 16836 0.7375.0 102 C83 3.6 30477 1.97 260.9 132 C84 0.6 20471 0.26 24.9 95 C8529000 C86 0.5 26017 0.27 14.1 53 C87 0.68 197.9 289 C88 1.1 34277 C891.1 37238 1.09 36.5 34 C90 2.0 47114 0.35 91.9 262 C91 1.9 31009 0.67195.3 291 C92 1.5 17527 0.67 245.9 368 C93 16.9 50000 1.15 96.8 84 C9425.1 50000 6.21 360.7 58 C95 12.3 50000 2.52 460.6 183 C96 11.2 53728.27 958.0 116 C97 34.9 9548 14.66 1733.9 118 C98 2.0 8926 1.03 462.2450 C99 1.7 9444 0.52 349 669 C100 0.8 16230 C101 19.7 33530 C102 C103C104 1.4 19699 0.44 140.0 C105 3.0 13649 1.38 998.2 C106 1.7 18413 0.22106.8 C107 C108 3.3 22906 0.98 207.8 212 C109 1.2 15169 0.62 11.4 18

The data in Table 1 represents an average over time of each assay foreach compound. For certain compounds, multiple assays have beenconducted.

Example 112: Half-Life of Exemplary Compounds Nonclinical In VivoStudies

All nonclinical studies were conducted in accordance with the Guide forthe Care and Use of Laboratory Animals as adopted and promulgated by theU.S. National Institutes of Health, and were approved by theInstitution's Animal Care and Use Committee or local equivalent.

Test compound PK was determined in monkeys (Labcorp, Madison, Wis.)following a single-dose intravenous infusion for 30 minutes. The dosingvehicle was 10% N-methylpyrrolidone; 50% polyethylene glycol 300 and 40%water (pH 8.3) for intravenous administration in monkeys. Serial bloodsamples were collected at predose, 0.25, 0.48 (before end of infusion),0.58, 0.75, 1, 1.5, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hourspostdose (based on start of infusion) and plasma test compoundconcentrations were quantified using an LC-MS/MS method.

Plasma Bioanalysis

Nonclinical plasma samples were prepared by addition of 200 μl coldacetonitrile/internal standard solution to 96-well plates containing 50μl aliquots of each plasma sample. After protein precipitation, each ofthe supernatants (50 μl) were transferred to clean 96-well plates anddiluted with 450 μl of water. The sample injection volume was 2 μl.Samples were analyzed by a multiple reaction monitoring LC-MS/MS method.LC-MS system consisted of a Cohesive LX-2 multiplex with two identicalDIONEX UltiMate 3000 RS pumps, Hypersil Gold C18 HPLC column (50×2.1 mm,1.9 m particle size; Thermo Fisher Scientific), and the ABSciexQTRAP5500 Mass Spectrometer LC-MS/MS system. Chromatography wasperformed using 0.1% formic acid and 1% isopropyl alcohol in aqueoussolution (MP A), and 0.1% formic acid and 1% isopropyl alcohol inacetonitrile (MP B). The flow rate was maintained at 0.5 mL/min(gradient: 0-0.5 minutes, 5% MP B; 1.83 minutes, 30% MP B; 2.83-3.50minutes, 95% MP B; 3.5-5 minutes, 5% MP B).

Pharmacokinetic Analysis

Plasma PK parameters for test compounds in monkeys were estimated vianoncompartmental analysis using the software program Phoenix WinNonlin,version 6.3 (Pharsight Corporation, Mountain View, Calif.). Thefollowing plasma PK parameters were estimated in nonclinical species (asappropriate): observed peak plasma concentration (C_(max)), time toreach C_(max) (T_(max)), last quantifiable plasma concentration(C_(last)), tin, time of C_(last) (T_(last)), area under the plasmaconcentration-time curve (AUC) from time 0 to C_(last) (AUC_(last)), AUCfrom time 0 to infinity (AUC_(inf)), CL, mean residence time (MRT), andvolume of distribution at steady state (V_(ss)).

Abbreviations

AUC: area under the plasma concentration-time curve;

AUCinf: area under the plasma concentration-time curve from time 0 toinfinity;

CL: clearance;

Cmax: observed peak plasma concentration;

HPLC: high-performance liquid chromatography;

LC-MS/MS: liquid chromatography-tandem mass spectrometry;

PK: pharmacokinetic(s);

Tmax: time to reach peak plasma concentration;

Vss: volume of distribution at steady state;

Example No. Structure Cyno half-life (h) C109

4.7 C24

57 C25

55 C27

48 C29

32 C30

6 C31

9 C37

22 C44

29 C63

110 C72

51 C76

60

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification areincorporated herein by reference, in their entirety to the extent notinconsistent with the present description.

From the foregoing it will be appreciated that, although specificembodiments have been described herein for purposes of illustration,various modifications may be made without deviating from the spirit andscope of the disclosure. Accordingly, the disclosure is not limitedexcept as by the appended claims.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein Ar is C₆-C₁₀ arylor six to ten membered heteroaryl containing one, two or threeheteroatoms selected from N, O, and S; wherein the C₆-C₁₀ aryl or six toten membered heteroaryl is optionally substituted with 1-4 substituentsindependently selected from the group consisting of halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkyloxy; R¹ is H, C₁-C₃ alkyl orphenyl; R² is H or C₁-C₃ alkyl; R³ is H or C₁-C₃ alkyl; R⁴ and R⁵ areeach independently H, halogen, cyano, C₁-C₆ alkyl, C₁-C₆ alkyloxy,C₆-C₁₀ aryl, or six to ten membered heteroaryl containing one, two orthree heteroatoms selected from N, O, and S; wherein the C₁-C₆ alkyl,C₁-C₆ alkyloxy, C₆-C₁₀ aryl, or six to ten membered heteroaryl isoptionally substituted with one, two or three groups independentlyselected from halogen, C₁-C₃ alkyloxy, and C₁-C₃ haloalkyloxy; or R⁴ andR⁵ are joined together to form a 3-6 membered carbocyclic ring or 4-6membered heterocyclic ring comprising one heteroatom selected from N, O,and S; R⁶ is H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy or C₁-C₆ haloalkyl;R⁷ is H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy, or C₁-C₆ haloalkyl;R^(8A) and R^(8B) are independently H, C₁-C₃ alkyl or benzyl; and —X—Y—is —(CR^(13A)R^(13B))_(p)—CR⁹═CR¹⁰; wherein R⁹ is H, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkyloxy; R¹⁰ is H, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkyloxy; or R⁹ and R¹⁰ together withthe carbons to which they are attached form a phenyl or a 5-6 memberedheteroaromatic ring containing 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; wherein the phenyl or the 5-6 memberedheteroaromatic ring is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy; and eachR^(13A) and R^(13B) is independently H, halogen, C₁-C₆ alkyl, C₁-C₆alkyloxy; or C₁-C₆ haloalkyl; and p is 0 or
 1. 2. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundis of a Formula Ia:


3. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is of a Formula Ib:

4.-6. (canceled)
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Ar is a group of Formula:

wherein Z is N; n is 0, 1, 2, 3, or 4; and each R^(A) is independentlyhalogen, C₁-C₆ alkyl, and C₁-C₆ alkyloxy. 8.-13. (canceled)
 14. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Ar is

n is 1, 2, or 3, and each R^(A) is independently fluoro or chloro. 15.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein the compound has a Formula II:

wherein n is 0, 1, 2, 3, or 4; and each R^(A) is independently halogen,C₁-C₆ alkyl, and C₁-C₆ alkyloxy.
 16. The compound of claim 15, or apharmaceutically acceptable salt thereof, wherein the compound has aFormula IIa:


17. The compound of claim 15, or a pharmaceutically acceptable saltthereof, wherein the compound has a Formula IIb:


18. (canceled)
 19. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein —X—Y— is —CR^(13A)R^(13B)—CR⁹═CR¹⁰—.20. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein —X—Y— is —CH₂—CR⁹═CR¹⁰— or —CR⁹═CR¹⁰—. 21.-23.(canceled)
 24. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁹ is H or halogen; and R¹⁰ is H or halogen; or R⁹and R¹⁰ together with the carbons to which they are attached form aphenyl, wherein the phenyl is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃ alkyloxy.
 25. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁹ is H or halogen; and R¹⁰ is H or halogen; or R⁹ and R¹⁰together with the carbons to which they are attached form a phenyl,wherein the phenyl is optionally substituted with one substituentselected from the group consisting of halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, and C₁-C₃ alkyloxy.
 26. (canceled)
 27. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundhas a Formula III:

wherein m is 0, 1, 2, or 3; and each R^(B) is independently halogen,C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₁-C₃ alkyloxy.
 28. The compound ofclaim 27, or a pharmaceutically acceptable salt thereof, wherein thecompound has a Formula IIIa:


29. The compound of claim 27, or a pharmaceutically acceptable saltthereof, wherein the compound has a Formula IIIb:


30. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound has a Formula IV:

wherein z is 0 or
 1. 31. The compound of claim 30, or a pharmaceuticallyacceptable salt thereof, wherein the compound has a Formula IVa:


32. The compound of claim 30, or a pharmaceutically acceptable saltthereof, wherein the compound has a Formula IVb.


33. The compound of claim 30, or a pharmaceutically acceptable saltthereof, wherein each R⁹ and R¹⁰ is independently H, halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkyloxy.
 34. (canceled)
 35. Thecompound of claim 34, or a pharmaceutically acceptable salt thereof,wherein each R⁹ and R¹⁰ is independently H or halogen.
 36. The compoundof claim 30, or a pharmaceutically acceptable salt thereof, wherein z is0.
 37. (canceled)
 38. The compound of claim 30, or a pharmaceuticallyacceptable salt thereof, wherein: z is 0; R¹, R², and R³ are each H; R⁴and R⁵ are independently H, halogen, cyano, C₁-C₆ alkyl, C₁-C₆ alkyloxy,C₆-C₁₀ aryl, or six to ten membered heteroaryl containing one, two orthree heteroatoms selected from N, O, and S; R⁶ and R⁷ are independentlyH, halogen, C₁-C₆ alkyl, C₁-C₆ alkyloxy or C₁-C₆ haloalkyl; R^(8A) andR^(8B) are both H; R⁹ and R¹⁰ is each independently H, halogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl; each R^(A) is independently fluoro or chloro;n is 1, 2, or
 3. 39. The compound of claim 30, or a pharmaceuticallyacceptable salt thereof, wherein: z is 0; R¹, R², and R³ are each H; R⁴and R⁵ are independently H, halogen, cyano, C₁-C₆ alkyl, or C₁-C₆alkyloxy; R⁶ and R⁷ are independently H, halogen, C₁-C₆ alkyl, C₁-C₆alkyloxy or C₁-C₆ haloalkyl; R^(8A) and R^(8B) are both H; R⁹ and R¹⁰ iseach independently H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; eachR^(A) is independently fluoro or chloro; n is 1, 2, or
 3. 40. Thecompound of claim 30, or a pharmaceutically acceptable salt thereof,wherein: z is 0; R¹, R², and R³ are each H; R⁴ and R⁵ are independentlyH, halogen, or C₁-C₆ alkyl; R⁶ and R⁷ are independently H, halogen orC₁-C₆ alkyl; R^(8A) and R^(8B) are both H; R⁹ and R¹⁰ is eachindependently H, halogen or C₁-C₆ alkyl; each R^(A) is independentlyfluoro or chloro; n is 1, 2, or
 3. 41.-48. (canceled)
 49. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, whereinR^(8B) is H and R^(8A) is H.
 50. (canceled)
 51. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R³ is H.
 52. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ and R² are both H.
 53. (canceled)
 54. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H orC₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one,two or three groups independently selected from halogen, C₁-C₃ alkyloxy,or C₁-C₃ haloalkyloxy; and R⁵ is H or C₁-C₆ alkyl.
 55. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is Hor C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted withone two or three groups independently selected from halogen, C₁-C₃alkyloxy, and C₁-C₃ haloalkyloxy; and R⁵ is H.
 56. compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R⁴ and R⁵ areindependently H, Me, OMe, or —CH₂F.
 57. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ and R⁵ are joinedtogether to form a 4-6 membered heterocyclic ring comprising oneheteroatom selected from N, O, and S.
 58. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁶ is H, halogen,C₁-C₆ alkyl, or C₁-C₆ haloalkyl.
 59. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁶ is H, C₁-C₆ alkyl,or C₁-C₆ haloalkyl.
 60. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁶ is H, methyl, or CH₂F. 61.-65.(canceled)
 66. The compound of om claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ is H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl. 67.-70. (canceled)
 71. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(13A) and R^(13B)are each independently H, halogen, C₁-C₆ alkyl, or C₁-C₆ alkyloxy. 72.(canceled)
 73. (canceled)
 74. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(13A) and R^(13B)are each independently H, fluoro, or methoxy. 75.-93. (canceled)
 94. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1, or pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient. 95.-100. (canceled)
 101. Akit comprising a compound of claim 1, or a pharmaceutically acceptablesalt thereof, and instructions for use. 102.-106. (canceled)
 107. Amethod of treating an HIV infection in a human having or at risk ofhaving the infection, comprising administering to the human atherapeutically effective amount of a compound of claim 1, orpharmaceutically acceptable salt thereof. 108.-135. (canceled)
 136. Thecompound of claim 40, or the pharmaceutically acceptable salt thereof,wherein R⁴ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionallysubstituted with one, two, or three groups independently selected fromhalogen, C₁-C₃ alkyloxy, and C₁-C₃ haloalkyloxy, R⁵ is H; R⁶ is halogenor C₁-C₆ alkyl; and R⁷ is H.